Methods for treating ischemic reperfusion injury with an angiotensin derivative polypeptide

Abstract

This disclosure provides methods for treating ischemic reperfusion injury. In particular, provided herein are methods for reducing the effects of and / or treating cardiac ischemic reperfusion injury comprising administering a therapeutic composition (e.g., an angiotensin derivative polypeptide). In some embodiments, the method comprises administering an angiotensin derivative polypeptide to a subject during, and / or after a cardiac ischemic event.

Description

[0001] UAZ-42224.601 UA23-296 METHODS FOR TREATING ISCHEMIC REPERFUSION INJURY WITH AN ANGIOTENSIN DERIVATIVE POLYPEPTIDE CROSS-REFERENCE TO RELATED APPLICATIONS The present application claims priority to U.S. Provisional Application No. 63 / 571,487, filed March 29, 2024, which is incorporated herein by reference in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under Grant No. AG066623 awarded by National Institutes of Health. The government has certain rights in the invention. SEQUENCE LISTING The text of the computer readable sequence listing filed herewith, titled “UAZ_42224_601_SequenceListing.xml”, created March 28, 2025, having a file size of 27,234 bytes, is hereby incorporated by reference in its entirety. FIELD OF THE INVENTION This disclosure provides methods for treating ischemic reperfusion injury. In particular, provided herein are methods for reducing the effects of and / or treating cardiac ischemic reperfusion injury comprising administering a therapeutic composition (e.g., an angiotensin derivative polypeptide). In some embodiments, the method comprises administering an angiotensin derivative polypeptide to a subject during, and / or after a cardiac ischemic event. BACKGROUND Ischemic heart disease remains the leading causes of death globally[1]. Coronary artery disease and myocardial infarction (MI) are the primary underlying causes of ischemic heart disease and represent over 50% of all-cause CVD morbidities that increases even more with age[2-4]. To this day, early revascularization after MI remains the most effective strategy to salvage ischemic myocardium, minimize cardiac damage and prevent HF [5-7]. However, revascularization, or reperfusion, of ischemic cardiac tissue exacerbates cardiac injury early on. Ischemic reperfusion (IR) injury is multifaceted and includes proliferation of UAZ-42224.601 UA23-296 reactive oxidative species (ROS), calcium overload, and inflammatory responses all contributing to increased damage [1, 8]. Further loss of myocardium from IR injury results in more extensive scarring, metabolic alterations, and more extreme morphological changes, such as wall thinning and stiffening, and disruption of synchronized wall contractions. Currently, there are limited to no available therapies that attenuate IR injury, suppress IR injury inflammation and stimulate beneficial post-IR cardiac function and repair. Improved therapeutic strategies for treating IR injury, IR injury inflammation, and stimulating post-IR cardiac function and repair. The present invention addresses these needs. SUMMARY Detection of subacute cardiac abnormalities prior to development of classical heart failure (HF) symptoms is essential to mitigating irreversible heart damage, identifying individuals at risk, and understanding preventative therapies for IR injury. Two-dimensional speckle tracking with strain analysis provides noninvasive indices to determine subacute myocardial dysfunction with greater accuracy than ejection fraction (EF) [9, 10]. Previous studies indicate that Global Longitudinal Strain (GLS) is a more sensitive prognostic indicator than left ventricular EF for predicting clinical outcomes and pathological remodeling in patients with acute MI

[0011] . Strain is a measure of tissue deformation during the cardiac cycle in one dimension, which is typically homogeneously distributed in healthy, non-ischemic myocardium [9, 12]. Considering the localized nature of ischemic cardiac tissue following MI, strain analysis provides a sensitive means for detecting not only defects in GLS, but also regional myocardial dysfunction. For example, strain analysis is strongly correlated to measures of cardiac function and objectively predicts alterations in wall morphology, such as scarring and increased fibrosis, a key characteristic of IR injury

[0013] . Mas receptor (MasR) activation via Ang-(1-7) imparts cardioprotective effects by decreasing ROS, inhibiting proinflammatory cytokine production, inhibiting fibrosis, and promoting vasodilation [14-16]. Further, increases in Ang-(1-7) activity and concentration with angiotensin receptor blockers (ARBs) improve EF post-MI

[0017] . PNA5, a novel synthetic glycopeptide derivative of Ang-(1-7), that has an improved half-life, has been shown to decrease circulating inflammatory cytokines 8-weeks post MI, and inhibit endothelial ROS production. Additionally, it has been established that PNA5 and Ang-(1-7) do not negatively affect cardiac function or cardiac morphology in healthy animals

[0014] . UAZ-42224.601 UA23-296 Considering cardioprotective properties of Ang-(1-7) and validation that PNA5 acts as a MasR ligand, it was predicted that PNA5 will attenuate IR injury and IR injury sequelae post-MI compared to untreated control animals. To overcome the limitations of using EF as a measure of systolic function such as load and heart rate dependence, experiments conducted during the course of developing embodiments for the present invention employed strain analysis using speckle tracking-based echocardiography (STE) to improve the sensitivity and specificity of how PNA5 treatment impacts IR injury. To this end, it was demonstrated that PNA5 treatment protects against loss of global longitudinal strain and prevents dyssynchrony in the longitudinal, radial and circumferential planes. Regional defects detected by strain analysis correlated with infarct size and cardiac remodeling post-MI ad may provide better and earlier prognostic indicators of beneficial cardiac outcomes. Although Ang-(1-7) and Ang-(1-7) derivatives have already shown therapeutic potential for preventing IR injury [18, 19], the experiments described herein provide evidence of how MasR agonism using PNA5 positively impacts global and regional strain parameters post-IR. Accordingly, this disclosure provides methods for treating ischemic reperfusion injury. In particular, provided herein are methods for treating ischemic reperfusion injury comprising administering a therapeutic agent, e.g., an angiotensin derivative polypeptide. In one aspect, the present disclosure provides a method of reducing the effects of and / or treating cardiac ischemic reperfusion injury in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an oligopeptide that is a non-naturally-occurring angiotensin-(1-7) derivative polypeptide, i.e., “Ang-(1-7) derivative.” In one aspect, the present disclosure provides a method of decreasing infarct size in a subject following ischemic reperfusion injury, comprising administering a therapeutically effective amount of an Ang-(1-7) derivative. In one aspect, the present disclosure provides a method of decreasing ischemic reperfusion injury related ventricle fibrosis in a subject following ischemic reperfusion injury, comprising administering a therapeutically effective amount of an Ang-(1-7) derivative. In one aspect, the present disclosure provides a method of decreasing ischemic reperfusion injury related heart tissue inflammation in a subject following ischemic reperfusion injury, comprising administering a therapeutically effective amount of an Ang-(1- 7) derivative. UAZ-42224.601 UA23-296 In one aspect, the present disclosure provides a method of decreasing ischemic reperfusion injury related cardiac function deterioration in a subject following ischemic reperfusion injury, comprising administering a therapeutically effective amount of an Ang-(1- 7) derivative. In one aspect, the present disclosure provides a method of decreasing ischemic reperfusion injury related memory impairment in a subject following ischemic reperfusion injury, comprising administering a therapeutically effective amount of an Ang-(1-7) derivative. In one aspect, the present disclosure provides a method of increasing heart function, reducing mortality, reducing cardiac volumes and / or reducing scar size in a subject following ischemic reperfusion injury, comprising administering a therapeutically effective amount of an Ang-(1-7) derivative. In one aspect, the present disclosure provides a method of repurfusing cardiac tissue in a subject following ischemic reperfusion injury, comprising administering a a therapeutically effective amount of an Ang-(1-7) derivative. In one aspect, the present disclosure provides a method of treating myocardial infarction in a subject following ischemic reperfusion injury, comprising administering a therapeutically effective amount of an Ang-(1-7) derivative. In some embodiments, the myocardial infarction is a cardiac ischemic event. In one aspect, the present disclosure provides a method of inducing cardiomyocyte regeneration, cardiac repair, vasculogenesis and / or cardiomyocyte differentiation in a subject following ischemic reperfusion injury, comprising administering a therapeutically effective amount of an Ang-(1-7) derivative. In some aspects, the Ang-(1-7) derivative is comprised within a pharmaceutical composition. In some aspects, administering the therapeutically effective amount of an Ang-(1-7) derivative occurs during or after the cardiac ischemic event. In some aspects, administering the therapeutically effective amount of an Ang-(1-7) derivative occurs concurrent with reperfusion of ischemic cardiac tissue. In some aspects, the therapeutically effective amount of an Ang-(1-7) derivative is administered about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 UAZ-42224.601 UA23-296 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, about 96 hours, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, or about 20 days, after reperfusion of ischemic cardiac tissue. In some aspects, the therapeutically effective amount of an Ang-(1-7) derivative is repeatedly administered to the subject, optionally the repeated administration comprises administration of one or more additional doses of the therapeutically effective amount of an Ang-(1-7) derivative to the subject. In some aspects, the repeated administration comprises administration of one or more additional doses of the therapeutically effective amount of an Ang-(1-7) derivative to the subject about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, about 96 hours, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, and / or about 20 days, after reperfusion of ischemic cardiac tissue. In some aspects, the methods further comprise administrating an effective amount of at least one additional therapeutic agent or at least one additional therapy to the subject for a combination therapy. In some aspects, each of the therapeutically effective amount of an Ang-(1-7) derivative and the at least one additional therapeutic agent or therapy is administered in a separate formulation or are administered together in a single formulation. In some asepcts, the therapeutically effective amount of an Ang-(1-7) derivative and the at least one additional therapeutic agent or therapy are administered sequentially, are administered concomitantly, and / or are administered in rotation. In some aspects, the at least one additional therapeutic agent or therapeutic therapy is selected from the group consisting of Idebenone, Eplerenone, VECTTOR, AVI-4658, UAZ-42224.601 UA23-296 Ataluren / PTC124 / Translarna, BMN044 / PRO044, CAT-1004, microDystrophin AAV gene therapy (SGT-001), Galectin-1 therapy (SB-002), LTBB4 (SB-001), rAAV2.5-CMV- minidystrophin, glutamine, NFKB inhibitors, sarcoglycan, delta (35 kDa dystrophin- associated glycoprotein), insulin like growth factor-1 (IGF-1) expression, genome editing through the CRISPR / Cas9 system, any gene delivery therapy aimed at reintroducing a functional recombinant version of the dystrophin gene, Exon skipping therapeutics, read- through strategies for nonsense mutations, cell-based therapies, utrophin upregulation, myostatin inhibition, anti-inflammatories / anti-oxidants, mechanical support devices, a biologic drug, a gene therapy or therapeutic gene modulation agent, any standard therapy for muscular dystrophy, and combinations thereof. In some aspets, the at least one additional therapeutic agent or therapeutic therapy is selected from the group comprising a percutaneous coronary intervention, coronary artery bypass grafting, thrombolytic therapy, anti-platelet therapy, heparin, warfarin, fibrinolytics, oxygen therapy, a vasodilator, pain medication, a beta blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB), a glycoprotein antagonist, a statin, an aldosterone antagonist, an implantable cardiac defibrillator (ICD), or any combination thereof. In some aspects, reperfusion of ischemic cardiac tissue comprises a percutaneous coronary intervention, coronary artery bypass grafting, thrombolytic therapy, anti-platelet therapy, heparin, warfarin, fibrinolytics, oxygen therapy, a vasodilator, pain medication, a beta blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB), a glycoprotein antagonist, a statin, an aldosterone antagonist, an implantable cardiac defibrillator (ICD), or any combination thereof. In some aspects, the subject is a mammal, optionally a human. In some aspects, the subject has or is suspected of having a cardiac disease, wherein the cardiac disease is myocardial infarction, ischemic heart disease, dilated cardiomyopathy, heart failure (e.g., congestive heart failure), ischemic cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, alcoholic cardiomyopathy, viral cardiomyopathy, tachycardia-mediated cardiomyopathy, stress-induced cardiomyopathy, amyloid cardiomyopathy, arrhythmogenic right ventricular dysplasia, left ventricular noncompaction, endocardial fibroelastosis, aortic stenosis, aortic regurgitation, mitral stenosis, mitral regurgitation, mitral prolapse, pulmonary stenosis, pulmonary regurgitation, tricuspid stenosis, tricuspid regurgitation, congenital disorder, genetic disorder, or any combination thereof. UAZ-42224.601 UA23-296 In some aspects, the subject is affected by a condition selected from the group comprising alcoholic cardiomyopathy, coronary artery disease, congenital heart disease, nutritional diseases affecting the heart, ischemic cardiomyopathy, hypertensive cardiomyopathy, valvular cardiomyopathy, inflammatory cardiomyopathy, cardiomyopathy secondary to a systemic metabolic disease, dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), restrictive cardiomyopathy (RCM), noncompaction cardiomyopathy, supravalvular aortic stenosis (SVAS), vascular scarring, atherosclerosis, chronic progressive glomerular disease, glomerulosclerosis, progressive renal failure, vascular occlusion, hypertension, stenosis, diabetic retinopathy, or any combination thereof. In some aspects, the cardiac ischemic reperfusion injury comprises cardiac ischemic damage, cardiac reperfusion injury, or a combination thereof. In some aspects, administering the therapeutically effective amount of an Ang-(1-7) derivative reduces cardiac ischemic damage, cardiac reperfusion injury, or a combination thereof, as compared to a control subject. In some aspects, the cardiac ischemic reperfusion injury comprises injuries caused by the cardiac ischemia event, reperfusion injuries, or a combination thereof. In some aspects, the cardiac ischemic event comprises one or more of myocardial infarction, coronary artery bypass grafting (CABG), cardiac bypass surgery, cardiac transplantation, and angioplasty. In some aspects, the cardiac ischemic event comprises a vascular interventional procedure employing a stent, laser catheter, atherectomy catheter, angioscopy device, beta or gamma radiation catheter, rotational atherectomy device, coated stent, radioactive balloon, heatable wire, heatable balloon, biodegradable stent strut, a biodegradable sleeve, or any combination thereof. In some aspects, the administration results in one or more of (1) increased survival as compared to a control subject, (2) improved kidney function of the subject as compared to a control subject, (3) a decrease in blood urea nitrogen (BUN) levels as compared to a control subject, (4) a reduced scarring in the left ventricle of the subject and / or improved regional wall motion in the left ventricle of the subject as compared to a control subject, (5) a decrease in end diastolic volume and / or end systolic volume as compared to a control subject, (6) an increase in ejection fraction as compared to a control subject, (7) an increase in the number of cardiomyocytes and / or mRNAs encoding proteins that are involved in differentiated cardiomyocyte muscle structure and function as compared to a control subject, (8) an increase UAZ-42224.601 UA23-296 in the mRNA levels and / or protein levels of one or more of Ank2, Kdm6a, Grk6, K1h115, Adam22, Pfkp, Gorasp2, Ralgps1, Inppl1, Kdm3a, Kit, Sort1, Dv12, Sema6d, Tead1, B4galnt2, Ltbp4, Osbp19, Nfe2I1, Tnnt2, and Fhl1 as compared to a control subject, and (9) a decrease in the mRNA levels and / or protein levels of one or more of Asph, Map6, Zfp120, Ctnndl, Eya3, Tnnt2, Kdm3a, Myo18a, Ncoa6, Slc25a13, Rpe, Ralgps1, Gimap1, Myo5a, Zeb2, Arap1, Nt5c2, Phldb1, Ttn, Camta2, Mef2c, Slk, Uimc1, Mthfd1I, Mtus1, Ythdc1, and Eif2ak4 as compared to a control subject, and (10) an increase in one of more of cardiomyocyte formation, cardiomyocyte proliferation, cardiomyocyte cell cycle activation, mitotic index of cardiomyocytes, myofilament density, borderzone wall thickness, or any combination thereof, as compared to a control subject. In some aspects, administering the therapeutically effective amount of an Ang-(1-7) derivative induces endogenous cardiomyocyte regeneration. In some aspects, administering the therapeutically effective amount of an Ang-(1-7) derivative enhances cardiac function in the subject as compared to a control subject, wherein enhancing cardiac function comprises one or more of (i) improving left ventricular function, (ii) improving fractional shortening, (iii) improving ejection fraction, (iv) reducing end- diastolic volume, (v) decreasing left ventricular mass, and (v) normalizing of heart geometry, or (vi) a combination thereof. In some aspects, administering the therapeutically effective amount of an Ang-(1-7) derivative has no significant effect on body weight and / or heart weight. In some aspects, administering the therapeutically effective amount of an Ang-(1-7) derivative does not cause one or more of arrhythmia, after contractions (AC), and contraction failure (CF). The naturally-occurring Ang(1-7) polypeptide has the amino acid sequence Asp-Arg- Val-Tyr-Ile-His-Pro (SEQ ID NO: 2). The term “Ang-(1-7) derivative” refers to oligopeptide in which one or more amino acid residue is either modified or different than the amino acid residue of the corresponding native Ang-(1-7). In some embodiments, the Ang-(1-7) derivatives have seven or eight amino acids and have biological activity as an agonist of the Mas receptor. In some aspects, the Ang-(1-7) derivative is of the formula: A1–A2–A3–A4–A5–A6– A7–A8(SEQ ID NO:1), where A1is selected from the group consisting of aspartic acid, glutamic acid, alanine, and glycosylated forms thereof; A2is selected from the group consisting of arginine, histidine, lysine, and glycosylated forms thereof; A3is selected from the group consisting of valine, alanine, isoleucine, leucine, and glycosylated forms thereof; UAZ-42224.601 UA23-296 A4is selected from the group consisting of tyrosine, phenylalanine, tryptophan, and glycosylated forms thereof; A5is selected from the group consisting of isoleucine, valine, alanine, leucine, and glycosylated forms thereof; A6is selected from the group consisting of histidine, arginine, lysine, and glycosylated forms thereof; A7is selected from the group consisting of proline, glycine, serine, and glycosylated forms thereof; and A8can be present or absent, wherein when A8is present, A8is selected from the group consisting of serine, threonine, hydroxyproline, and glycosylated forms thereof, provided (i) at least one of A1-A8is optionally substituted with a mono- or di-carbohydrate; or (ii) when A8is absent: (a) at least one of A1-A7is substituted with a mono- or di-carbohydrate, (b) A7is terminated with an amino group, or (c) a combination thereof. In some aspects, carbohydrate comprises glucose, galactose, xylose, fucose, rhamnose, lactose, cellobiose, melibiose, or a combination thereof. In other aspects, A8is serine or a glycosylated form thereof, or A8is absent and A7is serine or a glycosylated form thereof. In some embodiments, only the C-terminal amino acid is glycosylated (e.g., A8or A7when A8is absent). In some aspects, (i) A8is terminated with an amino group; or (ii) when A8is absent, A7is terminated with an amino group. Within these embodiments, in some instances (i) A8is serine that is optionally glycosylated (e.g., with glucose or lactose); or (ii) when A8is absent, A7is serine that is optionally glycosylated (e.g., with glucose or lactose). Still in other instances, when A8is absent and A7serine that is glycosylated with glucose. Within the latter instances, in some cases A7is terminated with an amino group. In some embodiments, whether or not the Ang(1-7) derivative is terminated with an amino group, the C-terminal amino acid (A8or A7when A8is absent) is the only glycosylated amino acid. In some aspects, A1is aspartic acid; A2is arginine; A3is valine; A4is tyrosine; A5is isoleucine; A6is histidine; and (i) A8is absent and A7is terminated with an amino group or A7is a glycosylated serine, or (ii) A8is serine terminated with an amino group. Within these embodiments, in some cases A8is a glycosylated serine. Still in other cases, A8is absent and A7is a glycosylated serine that is terminated with an amino group. In some aspects, the Ang-(1-7) derivative is a glycosylated Ang-(1-7) derivative having eight amino acids or less, typically seven or eight amino acids (e.g., amino acid residues). In some embodiments, the glycosylated Ang-(1-7) derivative is glycosylated with xylose, fucose, rhamnose, glucose, lactose, cellobiose, melibiose, or a combination thereof. UAZ-42224.601 UA23-296 Still in other embodiments, the carboxylic acid end of said glycosylated Ang-(1-7) derivative is substituted with an amino group. In some aspects, the Ang-(1-7) derivative is “PNA2.” PNA2 refers to an Ang(1-7) derivative of SEQ ID NO: 3, which is has the amino acid sequence of native Ang(1-7) except that Pro7comprises a C-terminal amidation (NH2). In some aspects, the Ang-(1-7) derivative is “PNA3.” PNA3 refers to an Ang(1-7) derivative of SEQ ID NO: 9, which is has the amino acid sequence of native Ang(1-7) with the addition of a serine at the C-terminus (i.e., Ser8) and wherein Ser8is glucosylated and comprises a C-terminal amidation (NH2). In some aspects, the Ang-(1-7) derivative is “PNA4.” PNA4 refers to an Ang(1-7) derivative of SEQ ID NO: 9, which is has the amino acid sequence of native Ang(1-7) with the addition of a serine at the C-terminus (i.e., Ser8) and wherein Ser8is lactosylated and comprises a C-terminal amidation (NH2). In some aspects, the Ang-(1-7) derivative is “PNA5.” PNA5 refers to an Ang(1-7) derivative of SEQ ID NO: 13, which is has the amino acid sequence of native Ang(1-7) except that Pro7is substituted by Ser7and wherein Ser7is glucosylated and comprises a C- terminal amidation (NH2). In some aspects, the Ang-(1-7) derivative is shown in Table 1. Table 1 sets forth some particularly useful Ang(1-7) derivative polypeptides but is not intended to be limiting on the scope of the invention. Table 1. Amino Acid Position SEQ O: UAZ-42224.601 UA23-296 Asp Arg Val Tyr Ile His Ser°* --- 13 Ala Arg Val Tyr Ile His Pro --- 14 , alternative. - = unmodified ° = glycosylated * = carboxy terminal NH2 BRIEF DESCRIPTION OF DRAWINGS FIG.1: Conventional echocardiography and PLAX STE strain analysis. Conventional PLAX Transthoracic Echocardiography (TTE) at 2 weeks (TTE1), 5 weeks (TTE2) and 8 weeks (TTE3) post-IR: (A) Ejection Fraction (EF%), (B) End Diastolic volume (EDV) and UAZ-42224.601 UA23-296 (C) End Systolic Volume (ESV). Line plot representation of Saline- (circles) and PNA5- (squares) treated mice at timepoints TTE1, TTE2, and TTE3 for (D) Global longitudinal strain (GLS), (E) Peak Strain (PK%; the highest segmental strain value) at the Base Anterior and (F) PK% at Base Posterior LV walls (Saline, n= 12; PNA5, n= 13). A 2-way repeated measures ANOVA followed by multiple comparisons to determine differences among each experimental group and timepoint. P values of <0.05 were considered statistically significant indicated within each plot. FIG.2: PNA5 does not impact cardiac function measured by conventional and speckle tracking-based strain echocardiography. (A) Ejection Fraction (EF%) over the course of 12 weeks in Sham+Saline and Sham+PNA5. (B) Scatter dot plot of measured EF% comparing Sham controls to both Saline- (circles) and PNA5- (squares) treated mice post-MI at TTE1. (C) Scatter dot plot comparing Global longitudinal strain (GLS) in Sham controls to both Saline- (circles) and PNA5- (squares) treated mice post-MI at TTE1. Significance was determined using one-way ANOVA with Tukey's multiple comparisons test; p-values ≤ 0.05 were considered significant. FIG.3: PNA5 protects against longitudinal dyssynchrony post-IR measured by time to peak strain. Line plot representation showing time to peak strain (T2P, ms) of Saline- (red circles) and PNA5- (blue squares) treated mice at timepoints TTE1, TTE2, and TTE3 in the following segments, MID: Anterior (A), MID: Posterior (B), APEX: Anterior (C), APEX: Posterior (D). A 2-way repeated measures ANOVA followed by multiple comparisons to determine differences among each experimental group and timepoint. P values of <0.05 were considered statistically significant indicated within each plot. FIG.4: PNA5 decreased inflammatory marker, TNFɑ, post-MI. (A): Scatter dot plot of mean fluorescence intensity of Tumor Necrosis Factor alpha (TNFɑ) in the infarct area. (B): Scatter dot plot of mean fluorescence intensity of TNFɑ in the total LV area. (Bottom panel) Representative images show Saline (left panel) and PNA5 (right panel). DAPI-stained nuclei appear blue (20ms exposure). TNFɑ appears red (Cy5; 400ms exposure time). Images were taken at 10X. The scale bar is 2000µm. Significance was determined with students t- test, p-values ≤ 0.05 were considered significant. FIG.5: PNA5 protects against longitudinal dyssynchrony post-IR. Line plot representations of Saline- (circles) and PNA5- (squares) treated mice at timepoints TTE1, TTE2, and TTE3 for (A) Global longitudinal dyssynchrony and (B) Basal longitudinal dyssynchrony determined by the time-delay to peak strain (∆T2P; Saline, n= 12; PNA5, n= UAZ-42224.601 UA23-296 13). A 2-way repeated measures ANOVA followed by multiple comparisons to determine differences among each experimental group and timepoint. P values of <0.05 were considered statistically significant indicated within each plot. FIG.6: PNA5 protects against radial dyssynchrony post-IR (PLAX view). Line plot representations of Saline- (circles) and PNA5- (squares) treated mice at timepoints TTE1, TTE2, and TTE3 for (A) Radial dyssynchrony as ∆T2P and (B) Radial dyssynchrony calculated as the standard deviation of T2P (STD T2P; Saline, n= 12; PNA5, n= 13). A 2-way repeated measures ANOVA followed by multiple comparisons to determine differences among each experimental group and timepoint. P values of <0.05 were considered statistically significant indicated within each plot. FIG.7: PNA5 protects against radial dyssynchrony post-IR (short- axis view). Segmental radial synchronicity determined from the short axis view. Inset: Cartoon of cardiac short-axis view at the mid region; black arrow represents circumferential strain during systole and yellow arrow represents radial strain measured in the short-axis view. Line plot representations of Saline- (circles) and PNA5- (squares) treated mice at timepoints TTE1, TTE2, and TTE3 for (A) Radial dyssynchrony at mid wall (MID) as ∆T2P and (B) Radial dyssynchrony calculated as STD T2P; (C) Radial dyssynchrony at mid free wall (MID: Free Wall) as ∆T2P; (D) Basal radial dyssynchrony at septal wall (BASE: Septal) as ∆T2P. (Saline, n= 12; PNA5, n= 13). A 2-way repeated measures ANOVA followed by multiple comparisons to determine differences among each experimental group and timepoint. P values of <0.05 were considered statistically significant indicated within each plot. FIG.8: PNA5 protects against circumferential dyssynchrony post-IR. Inset: Cartoon of cardiac short-axis view at the mid region; black arrow represents circumferential strain during systole and yellow arrow represents radial strain measured in the short-axis view. Line plot representations of Saline- (circles) and PNA5- (squares) treated mice at timepoints TTE1, TTE2, and TTE3 measured at the base (BASE), mid (MID), and Apex (APEX) of the heart. Basal (BASE) circumferential dyssynchrony calculated as ∆T2P (A) and STD T2P (B) including basal circumferential dyssynchrony at the Free Wall (C). Mid (MID) circumferential dyssynchrony calculated as ∆T2P (D) and STD T2P (E) including Mid circumferential dyssynchrony (∆T2P) at the Septal (F) and Free Wall (G). Apical (APEX) circumferential dyssynchrony calculated as ∆T2P (H) and STD T2P (I) i FIG.9: PNA5 attenuated infarct size post-MI. (A) Scatter dot plot of absolute infarct area in PNA5-treated hearts relative to Saline-treated control hearts (*p=0.0111). (B) Scatter UAZ-42224.601 UA23-296 dot plot of absolute infarct area normalized to total left ventricular area (Infarct Area / LV Area) in PNA5- and Saline-treated hearts (**p=0.0036). (C) Total LV Area determined from PNA5- and Saline-treated hearts post-MI. (Saline, n= 12; PNA5, n= 13). A 2-way repeated measures ANOVA followed by multiple comparisons to determine differences among each experimental group and timepoint. P values of <0.05 were considered statistically significant indicated within each plot. FIG.10: PNA5 decreased inflammatory marker, Hif1ɑ, post-MI. (A): Scatter dot plot of mean fluorescence intensity of Hypoxia Inducible Factor 1 alpha (Hif1ɑ) in the infarct area. (B): Scatter dot plot of mean fluorescence intensity of Hif1ɑ in the total LV area. FIG.11: Global longitudinal strain correlated with total infarct area. (A): correlation between infarct size and global longitudinal strain (GLS) are shown over the course of TTE1 (2-weeks post IRI), TTE 2 (5-weeks post IRI), and TTE3 (8-weeks post IRI). (B): correlation between TNFɑ (Tumor necrosis factor alpha) normalized to total heart area mean fluorescent intensity and global longitudinal strain (GLS) are shown over the course of TTE1 (2-weeks post IRI), TTE 2 (5-weeks post IRI), and TTE3 (8-weeks post IRI). (C): Comparisons between TNFɑ and collagen content show a significant positive correlation. Simple linear regression was used to determine correlation and significance. P-values ≤ 0.05 were considered significant. FIG.12: PNA5 reverses cognitive impairment, post-MI. Cognitive function was tested by a novel object recognition test (NOR) as a discrimination ratio for control (0.178±0.091, n=5) and mice with ischemic reperfusion (IR) mice. IR mice were treated with either saline (-0.410±0.123, n=11) or PNA5 (0.236±0.139, n=10). The discrimination ratio is the measurement of cognitive abilities to recognize new objects from previously learned objects. A positive discrimination ratio is indicative of intact cognitive abilities. A negative discrimination ratio or a decreased discrimination ratio is indicative of cognitive impairment. IR mice treated with saline are significantly decreased compared to both control mice (p=0.0282) and IR-PNA5 treated mice (p=0.0028). Significance was tested via one-way ANOVA, followed by Tukey's multiple comparisons tests. P values <0.05 are considered significant. DEFINITIONS Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present UAZ-42224.601 UA23-296 disclosure belongs. See, e.g. Singleton et al., Dictionary of Microbiology and Molecular Biology 2nd ed., J. Wiley & Sons (New York, N.Y.1994); Sambrook et al., Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Press (Cold Spring Harbor, N.Y.1989). For purposes of the present disclosure, the following terms are defined below. The singular form “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a molecule” includes one or more molecules, including mixtures thereof. As used in this disclosure and the appended claims, the term “and / or” can be singular or inclusive. For example, “A and / or B” is used herein to include all of the following alternatives: “A”, “B”, and “A and B”. The term “about”, as used herein, has its ordinary meaning of approximately. If the degree of approximation is not otherwise clear from the context, “about” means either within plus or minus 10% of the provided value, or rounded to the nearest significant figure, in all cases inclusive of the provided value. Where ranges are provided, they are inclusive of the boundary values. “Administering” means providing a pharmaceutical agent or composition to a subject, and includes, but is not limited to, administering by a medical professional and self- administering. “Parenteral administration,” means administration through injection or infusion. Parenteral administration includes, but is not limited to, subcutaneous administration, intravenous administration, intramuscular administration, intra-arterial administration, and intracranial administration. “Subcutaneous administration” means administration just below the skin. “Intravenous administration” means administration into a vein. “Intraarterial administration” means administration into an artery. The term “amino acid” refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, γ- carboxyglutamate, and 0-phosphoserine. Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, e.g., an a carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refers to chemical UAZ-42224.601 UA23-296 compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid. The terms “non-naturally occurring amino acid” and “unnatural amino acid” refer to amino acid analogs, synthetic amino acids, and amino acid mimetics which are not found in nature. Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes. The terms “identical” or “percent identity”, in the context of two or more nucleic acids or proteins, refer to two or more sequences or subsequences that are the same or have a specified percentage of nucleotides or amino acids that are the same (e.g., about 60% sequence identity, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher identity over a specified region, when compared and aligned for maximum correspondence over a comparison window or designated region) as measured using a BLAST or BLAST 2.0 sequence comparison algorithms with default parameters described below, or by manual alignment and visual inspection. See e.g., the NCBI web site at ncbi.nlm.nih.gov / BLAST. Such sequences are then said to be “substantially identical.” This definition also refers to, or may be applied to, the complement of a test sequence. This definition also includes sequences that have deletions and / or additions, as well as those that have substitutions. Sequence identity typically exists over a region that is at least about 50 amino acids or nucleotides in length, or over a region that is 50-100 amino acids or nucleotides in length, or over the entire length of a given sequence. As used herein, the term “myocardial cell” includes any cell that is obtained from, or present in, myocardium such as a human myocardium and / or any cell that is associated, physically and / or functionally, with myocardium. In some embodiments disclosed herein, a myocardial cell is a cardiomyocyte. The term “native Ang-(1-7)” refers to the naturally-occurring Ang(1-7) polypeptide having the amino acid sequence Asp-Arg-Val-Tyr-Ile-His-Pro (SEQ ID NO: 2). The term “Ang-(1-7) derivative” refers to oligopeptide in which one or more amino acid residue is either modified or different than the amino acid residue of the corresponding native Ang-(1-7). The term “Ang-(1-7) derivative” also includes oligopeptide of eight amino acid residues as discussed in more detail below. UAZ-42224.601 UA23-296 By “PN-A2” is meant the Ang(1-7) derivative of SEQ ID NO: 3, which is has the amino acid sequence of native Ang(1-7) except that Pro7comprises a C-terminal amidation (NH2). By “PN-A3” is meant the Ang(1-7) derivative of SEQ ID NO: 9, which is has the amino acid sequence of native Ang(1-7) with the addition of a serine at the C-terminus (i.e., Ser8) and wherein Ser8is glucosylated and comprises a C-terminal amidation (NH2). By “PN-A4” is meant the Ang(1-7) derivative of SEQ ID NO: 9, which is has the amino acid sequence of native Ang(1-7) with the addition of a serine at the C-terminus (i.e., Ser8) and wherein Ser8is lactosylated and comprises a C-terminal amidation (NH2). By “PN-A5” is meant the Ang(1-7) derivative of SEQ ID NO: 13, which is has the amino acid sequence of native Ang(1-7) except that Pro7is substituted by Ser7and wherein Ser7is glucosylated and comprises a C-terminal amidation (NH2). The term “carbohydrate” refers to pentose and hexose of empirical formula (CH2O)n, where n is 5 for pentose and 6 for hexose. A carbohydrate can be monosaccharide, disaccharide, oligosaccharide (e.g., 3-20, typically 3-10, and often 3-5 monomeric saccharides are linked together), or polysaccharide (e.g., greater than 20 monomeric saccharide units). More often, the term carbohydrate refers to monosaccharide and / or disaccharide. However, it should be appreciated that the scope of the invention is not limited to mono- or di-saccharides. Often the terms “carbohydrate” and “saccharide” are used interchangeably herein. The term “oligopeptide” as used throughout the specification and claims is to be understood to include amino acid chain of any length, but typically amino acid chain of about fifteen or less, often ten or less, still more often eight or less, and most often seven or eight. It should be appreciated that one or more of the amino acids of Ang-(1-7) can be replaced with an “equivalent amino acid”, for example, L (leucine) can be replaced with isoleucine or other hydrophobic side-chain amino acid such as alanine, valine, methionine, etc., and amino acids with polar uncharged side chain can be replaced with other polar uncharged side chain amino acids. While Ang-(1-7) comprises 7 amino acids, in some embodiments the oligopeptide of the invention has eight or less amino acids. By “glycosylated,” is meant the covalent attachment to that amino acid of a mono-, di-, or polysaccharide. The glycosylation may be N-linked or O-linked, as appropriate. For example, N-linked glycosylation may occur at the R-group nitrogen in asparagine or arginine, and O-linked glycosylation may occur through the R-group hydroxyl of serine, threonine, and UAZ-42224.601 UA23-296 tyrosine. Suitable carbohydrates include, for example, monosaccharides such as glucose, galactose, fructose, xylose, ribose, arabinose, lyxose, allose, altrose, mannose, fucose, and rhamnose, disaccharides such as sucrose, lactose, maltose, trehalose, melibiose, cellobiose, higher-order structures such as sorbitol, mannitol, maltodextrins, and farinose, and amino sugars such as galactosamine and glucosamine. In some particular embodiments, the polypeptide is glycosylated with glucose, lactose, cellobiose, melibiose, β-D-glucose, β-D- lactose, β-D-cellobiose, or β-D-melibiose. The term “combinations thereof,” which reference to any modifications (e.g, carbohydrate modifications) of Ang-(1-7) derivatives refers to oligopeptides in which two, three, four, five, six, seven, or eight of the individual amino acids are modified by the attachment of a carbohydrate. For Ang-(1-7) derivatives having a plurality of carbohydrate modifications, the modifying carbohydrates may be the same on every modified amino acid, or the several modified amino acids may comprise a mixture of different carbohydrates. As used herein, “treatment” refers to a clinical intervention made in response to a disease, disorder or physiological condition manifested by a patient or to which a patient may be susceptible. The aim of treatment includes, but is not limited to, the alleviation or prevention of symptoms, slowing or stopping the progression or worsening of a disease, disorder, or condition and / or the remission of the disease, disorder or condition. “Treatments” refer to one or both of therapeutic treatment and prophylactic or preventative measures. Subjects in need of treatment include those already affected by a disease or disorder or undesired physiological condition as well as those in which the disease or disorder or undesired physiological condition is to be prevented. In some embodiments of the disclosure, the terms “treatment,” “therapy,” and “amelioration” refer to any reduction in the severity of symptoms, e.g., of a neurodegenerative disorder or neuronal injury. As used herein, the terms “treat” and “prevent” are not intended to be absolute terms. Treatment can refer to any delay in onset, amelioration of symptoms, and improvement in patient survival, increase in survival time or rate, etc., or a combination thereof. The effect of treatment can be compared to an individual or pool of individuals not receiving the treatment, or to the same patient prior to treatment or at a different time during treatment. In some embodiments, the severity of disease or disorder in an individual can be reduced by at least 10%, as compared, e.g., to the individual before administration or to a control individual not undergoing treatment. In some embodiments, the severity of disease or disorder in an individual is reduced by at least 25%, UAZ-42224.601 UA23-296 50%, 75%, 80%, or 90%, or in some embodiments, no longer detectable using standard diagnostic techniques. As used herein, the term “effective amount” or “therapeutically effective amount” refers to an amount sufficient to effect beneficial or desirable biological and / or clinical results. In some embodiments, the term refers to that amount of the therapeutic agent sufficient to ameliorate a given disorder or symptoms. For example, for the given parameter, a therapeutically effective amount can show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100% compared to a control. Therapeutic efficacy can also be expressed as “-fold” increase or decrease. For example, a therapeutically effective amount can have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over a control. The terms “subject,” “patient,” “individual in need of treatment” and like terms are used interchangeably and refer to, except where indicated, an mammal subject that is the object of treatment, observation, or experiment. As used herein, “mammal” refers to a subject belonging to the class Mammalia and includes, but not limited to, humans, domestic and farm animals, zoo animals, sports and pet animals. Non-limiting examples of mammals include humans, and non-human primates, mice, rats, sheep, dogs, horses, cats, cows, goats, pigs, and other mammalian species. In some embodiments, the mammal is a human. However, in some embodiments, the mammal is not a human. The term does not necessarily indicate that the subject has been diagnosed with a particular disease or disorder, but typically refers to a subject under medical supervision. “Subject suspected of having” means a subject exhibiting one or more clinical indicators of a disease or condition. As used herein, “comprising” is synonymous with “including,” “containing,” or “characterized by,” and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. As used herein, “consisting of” excludes any elements, steps, or ingredients not specified in the claimed composition or method. As used herein, “consisting essentially of” does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claimed composition or method. Any recitation herein of the term “comprising”, particularly in a description of components of a composition or in a description of steps of a method, is understood to encompass those compositions and methods consisting essentially of and consisting of the recited components or steps. In some embodiments of the methods or processes described herein, the steps can be carried out in any order, except when a temporal or operational sequence is explicitly recited. UAZ-42224.601 UA23-296 Furthermore, in some embodiments, the specified steps can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, in some embodiments a claimed step of doing X and a claimed step of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process. As will be understood by one having ordinary skill in the art, for any and all purposes, such as in terms of providing a written description, all ranges disclosed herein also encompass any and all possible sub-ranges and combinations of sub-ranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non- limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like include the number recited and refer to ranges which can be subsequently broken down into sub-ranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 articles refers to groups having 1, 2, or 3 articles. Similarly, a group having 1-5 articles refers to groups having 1, 2, 3, 4, or 5 articles, and so forth. DETAILED DESCRIPTION Ischemic heart disease typically by myocardial infarction (MI) is the leading cause of death. Ischemic reperfusion (IR) injury following MI is multifaceted, driven by reactive oxidative species (ROS), calcium overload, and inflammatory responses. A novel synthetic glycopeptide derivative of Angiotensin-(1-7), PNA5, has been shown to have an improved half-life, decrease circulating inflammatory cytokines post-MI, and inhibit endothelial ROS production. Experiments conducted during the course of developing embodiments for the present invention predicted that PNA5 will attenuate IR sequelae post-MI. Specifically, 3- month-old C57Bl / 6J male mice were subjected to IR and treated subcutaneously with PNA5 (100µg / kg / day, n=14) or saline (n=12) starting immediately after reperfusion and continued daily for eight-weeks. Echocardiograms were taken 2-, 5-, and 8-weeks post-IR in B-mode using the Vevo 2100 High-Resolution Imaging System (Visual Sonics, Toronto, Canada). Data were analyzed using Vevo 2100®analytic software. Hearts were stained for infarct size using 2-3-4-triphenyltetrazoliumchloride stain, fibrosis using Picrosirius Red, and UAZ-42224.601 UA23-296 inflammation via immunofluorescence for TNFα. Conventional transthoracic echocardiography showed early improvement in ejection fraction by 5 weeks post-IR. Using speckle tracking-based echocardiograph, it was demonstrated that PNA5 treatment improved parameters of strain and dyssynchrony in a regional and temporal manner. Along with a reduced infarct size by 9.7+ / -8.9%, PNA5 treatment improved cardiac remodeling evidenced by reduced scarring within the mid-apical regions of the heart. compared to the IR-saline- treated animals. These data indicate that PNA5 treatments improve heart outcomes post-IR and could potentially be a therapeutic for IR injury. Accordingly, this disclosure provides methods for treating ischemic reperfusion injury. In particular, provided herein are methods for reducing the effects of and / or treating cardiac ischemic reperfusion injury comprising administering a therapeutic composition (e.g., an angiotensin derivative polypeptide). In some embodiments, the method comprises administering an angiotensin derivative polypeptide to a subject during, and / or after a cardiac ischemic event. 1. Ang-(1-7) Derivatives The renin-angiotensin system (RAS), well known for roles in blood pressure regulation and fluid homeostasis, was recently implicated in metastatic bone disease including inflammation, angiogenesis, tumor cell proliferation, and migration. Angiotensin II (Ang II) is the major end product of the RAS through cleavage by Angiotensin Converting Enzyme (ACE). This nonapeptide binds to and activates two G-protein coupled receptors (GPCRs): angiotensin II receptor type 1 (AT1) and type 2 (AT2). Physiological effects such as vasoconstriction, inflammation, fibrosis, cellular growth / migration, and fluid retention are reported for AT1 and AT2. Ang II is cleaved by ACE2 to yield Angiotensin-(1-7) (Ang-(1- 7)), a biologically active heptapeptide. In contrast to Ang II, Ang-(1-7) binds to the GPCR, Mas receptor (MasR; Kd=0.83 nM) with 60-100 fold greater selectivity over the AT1 and AT2 receptors. Activation of the MasR elicits effects opposite to those of the Ang II / AT1 / AT2 axis including having anti-inflammatory and antidepressant activities. Some aspects of the invention provide oligopeptides that are derivatives of Ang-(1-7). As discussed above, the term “derivative” of Ang-(1-7) refers to an oligopeptide whose amino acid sequence of any one or more of Ang-(1-7) is modified (e.g., via methylation, presence of a functional group, such as hydroxy group on proline), attached to a carbohydrate, is replaced with corresponding D-amino acid or an “equivalent amino acid” as UAZ-42224.601 UA23-296 defined above, and / or the terminal amino group end or the carboxyl end of Ang-(1-7) is modified, for example, the carboxylic acid end can be modified to be an amide, an amine, a thiol, or an alcohol functional group, or one in which an additional amino acid residue is present compared to native Ang-(1-7). It should be appreciated that the term “Ang-(1-7) derivative” excludes the native Ang-(1-7), i.e., amino acid sequences of endogenous Ang-(1- 7) without any modification. In some embodiments, oligopeptides of the invention have the amino group on the carboxylic acid terminal end (i.e., the –OH group of the carboxylic acid is replaced with –NRaRb, where each of Raand Rbis independently hydrogen or C1-C6alkyl) and / or have one or more amino acid residues that are (i) replaced with a corresponding D-amino acid, (ii) glycosylated, (iii) replaced with another amino acid, (iv) or a combination thereof. In one particular embodiment, the oligopeptide of the invention is Ang-(1-7) derivative of the formula: A1–A2–A3–A4–A5–A6–A7–A8(SEQ ID NO:1), where A1is selected from the group consisting of aspartic acid, glutamic acid, alanine, and a derivative thereof; A2is selected from the group consisting of arginine, histidine, lysine, and a derivative thereof; A3is selected from the group consisting of valine, alanine, isoleucine, leucine, and a derivative thereof; A4is selected from the group consisting of tyrosine, phenylalanine, tryptophan, and a derivative thereof; A5is selected from the group consisting of isoleucine, valine, alanine, leucine, and a derivative thereof; A6is selected from the group consisting of histidine, arginine, lysine, and a derivative thereof; A7is selected from the group consisting of proline, glycine, serine, and a derivative thereof; and A8can be present or absent, wherein when A8is present, A8is selected from the group consisting of serine, threonine, hydroxyproline, and a derivative thereof, provided (i) at least one of A1-A8is optionally substituted with a mono- or di-carbohydrate; or (ii) when A8is absent: (a) at least one of A1-A7is substituted with a mono- or di-carbohydrate, (b) A7is terminated with an amino group, or (c) a combination thereof. In some embodiments, A1is the amino terminal end of the oligopeptide and A8(or A7when A8is absent) is the carboxyl terminal end. Still in other embodiments, A1is the carboxyl terminal end and A8(or A7when A8is absent) is the amino terminal end. Yet in other embodiments, the carboxylic acid functional group of the carboxyl terminal end is modified as an amide functional group, an amine functional group, a hydroxyl functional group, or a thiol functional group. The amide and the amine functional groups can be non- alkylate, mono-alkylated or di-alkylated. UAZ-42224.601 UA23-296 Yet in other embodiments, the carbohydrate comprises glucose, galactose, xylose, fucose, rhamnose, or a combination thereof. In some instances, the carbohydrate is a mono- carbohydrate, whereas in other instances, the carbohydrate is a di-carbohydrate. In other embodiments, at least one of A1-A8is substituted with a mono-carbohydrate. Still in other embodiments, at least one of A1-A8is substituted with a di-carbohydrate. It should be appreciated that the scope of the invention also includes those oligopeptides having both mono- and di-carbohydrates. Exemplary di-carbohydrates that can be used in oligopeptides of the invention include, but are not limited to, lactose, cellobiose, melibiose, and a combination thereof. However, it should be appreciated that the scope of the invention includes oligopeptides that are substituted with any dicarbohydrates known to one skilled in the art. In one particular embodiment, A8is serine or a derivative thereof. In some instances, the carboxylic acid moiety of the serine is modified as an amide or an amine. In one case, serine is terminated as an amino group. Still in other embodiments, the serine residue of A8is glycosylated with glucose or lactose. Yet in other embodiments, at least one, typically at least two, generally at least three, often at least four, still more often at least five, yet still more often at least six, and most often all of A1-A8is D-amino acid. Another aspect of the invention provides oligopeptides, such as Ang-(1-7) derivatives, having eight amino acids or less, typically seven or eight amino acid residues. In some embodiments, one or more amino acids have attached thereto a carbohydrate group. Often the carbohydrate group is attached to the oligopeptide via glycosylation. The carbohydrate can be attached to the oligopeptide via any of the side chain functional group of the amino acid or the amide group. Accordingly, the scope of the invention includes, but is not limited to, O-glycosylate, N-glycosylate, S-glycosylated oligopeptides. The term “X-glycosylated” refers to having a carbohydrate attached to the oligopeptide via the heteroatom “X” of the amino acid. For example, for serine whose side-chain functional group is hydroxyl, “O- glycosylated” means the carbohydrate is attached to the serine’s side-chain functional group, i.e., the hydroxyl group. Similarly, “N-glycosylation” of leucine refers to having the carbohydrate attached to the amino side-chain functional group of leucine. Typically, the glycosylation is on the side-chain functional group of the amino acid. In some embodiments, the Ang-(1-7) derivative is glycosylated with xylose, fucose, rhamnose, glucose, lactose, cellobiose, melibiose, or a combination thereof. UAZ-42224.601 UA23-296 Yet in other embodiments, the carboxylic acid terminal end of said glycosylated Ang- (1-7) derivative is substituted with an amino group. When referring to the carboxyl acid terminal end being substituted with an amino group, it means –OH group of the carboxylic acid is replaced with –NH2 group. Thus, the actual terminal end functional group is an amide, i.e., rather than having the oligopeptide being terminated at the carboxylic acid terminal end with a functional group –CO2H, the carboxylic acid terminal end is terminated with an amide group (i.e., –CO2NR’2, where each R’ is independently hydrogen or C1-C12alkyl). Still in other embodiments, the carboxylic acid terminal group is terminated with a hydroxyl or a thiol group. In some embodiments, the modified carboxylic acid terminal group is used to attach the carbohydrate, e.g., via glycosylation. Without being bound by any theory, it is believed that the oligopeptide of the invention that are glycosylated exploits the inherent amphipathicity of the folded Ang-(1-7) glycopeptides (i.e., glycosylated oligopeptides of the invention) and the “biousian approach” to deliver the glycosylated oligopeptides of the invention across the blood-brain barrier. In some instances, the amount of increase in crossing the blood-brain barrier by oligopeptides of the invention is at least 6%, typically at least 10%, and often at least 15% compared to native Ang-(1-7). In some instances, the amount of increase in the Cmax for oligopeptides of the invention in cerebral-spinal fluid is 2-10 fold, 3-8 fold, or 5-8 fold compared to native Ang- (1-7). In some instances, the amount of increase in the Cmax for oligopeptides of the invention in cerebral-spinal fluid is 2, 3, 4, 5, 6, 7, 8, 9 or 10 fold compared to native Ang-(1- 7). In other instances, oligopeptides of the invention have in vivo half-life of at least 20 min, at least 30 min, at least 40 min, at least 50 min, at least 60 min, or at least 2, hours, at least 3 hours, at least 4 hours, at least 5 hours or at least 6 hours. In some instances, the amount of increase in the in vivo half-life for oligopeptides of the invention is 2-30 fold, 3-25 fold, 4-20 fold, 4-10 fold, 10-25 fold, 15-25 fold, or 20-25 fold compared to native Ang-(1-7). Alternatively, compared to native Ang-(1-7), oligopeptides of the invention exhibit at least 50 fold, typically at least 75 fold, and often at least 100 fold increase in in vivo half-life. In some aspects, the Ang-(1-7) derivative is “PNA2.” PNA2 refers to an Ang(1-7) derivative of SEQ ID NO: 3, which is has the amino acid sequence of native Ang(1-7) except that Pro7comprises a C-terminal amidation (NH2). In some aspects, the Ang-(1-7) derivative is “PNA3.” PNA3 refers to an Ang(1-7) derivative of SEQ ID NO: 9, which is has the amino acid sequence of native Ang(1-7) with UAZ-42224.601 UA23-296 the addition of a serine at the C-terminus (i.e., Ser8) and wherein Ser8is glucosylated and comprises a C-terminal amidation (NH2). In some aspects, the Ang-(1-7) derivative is “PNA4.” PNA4 refers to an Ang(1-7) derivative of SEQ ID NO: 9, which is has the amino acid sequence of native Ang(1-7) with the addition of a serine at the C-terminus (i.e., Ser8) and wherein Ser8is lactosylated and comprises a C-terminal amidation (NH2). In some aspects, the Ang-(1-7) derivative is “PNA5.” PNA5 refers to an Ang(1-7) derivative of SEQ ID NO: 13, which is has the amino acid sequence of native Ang(1-7) except that Pro7is substituted by Ser7and wherein Ser7is glucosylated and comprises a C- terminal amidation (NH2). In some aspects, the Ang-(1-7) derivative is shown in Table 1. Table 1 sets forth some particularly useful Ang(1-7) derivative polypeptides but is not intended to be limiting on the scope of the invention. In another aspect, disclosed herein are embodiments of a therapeutic composition that includes an effective amount of at least one Ang-(1-7) derivative. 2. Methods of Use There are provided, in some embodiments, methods of reducing or treating cardiac ischemic reperfusion injury. In some embodiments, the method comprises: administering a therapeutic composition to a subject before, during, and / or after a cardiac ischemic event, wherein the therapeutic composition comprises one or more Ang-(1-7) derivatives. The method can comprise reperfusion of ischemic cardiac tissue. In one aspect, the present disclosure provides a method of decreasing infarct size in a subject following ischemic reperfusion injury, comprising administering a therapeutically effective amount of an Ang-(1-7) derivative. In one aspect, the present disclosure provides a method of decreasing ischemic reperfusion injury related ventricle fibrosis in a subject following ischemic reperfusion injury, comprising administering a therapeutically effective amount of an Ang-(1-7) derivative. In one aspect, the present disclosure provides a method of decreasing ischemic reperfusion injury related heart tissue inflammation in a subject following ischemic reperfusion injury, comprising administering a therapeutically effective amount of an Ang-(1- 7) derivative. UAZ-42224.601 UA23-296 In one aspect, the present disclosure provides a method of decreasing ischemic reperfusion injury related cardiac function deterioration in a subject following ischemic reperfusion injury, comprising administering a therapeutically effective amount of an Ang-(1- 7) derivative. In one aspect, the present disclosure provides a method of decreasing ischemic reperfusion injury related memory impairment in a subject following ischemic reperfusion injury, comprising administering a therapeutically effective amount of an Ang-(1-7) derivative. There are provided, in some embodiments, methods of treating myocardial infarction. In some embodiments, the method comprises: administering a therapeutic composition to a subject before, during, and / or after reperfusion of ischemic cardiac tissue, wherein the therapeutic composition comprises one or more of Ang-(1-7) derivatives. Myocardial infarction can be a cardiac ischemic event. There are provided, in some embodiments, methods of inducing cardiomyocyte regeneration, cardiac repair, vasculogenesis and / or cardiomyocyte differentiation following a cardiac ischemic event. In some embodiments, the method comprises: administering a therapeutic composition to a subject before, during, or after reperfusion of ischemic cardiac tissue, wherein the therapeutic composition comprises one or more Ang-(1-7) derivatives. Disclosed herein include methods increasing heart function, reducing mortality, reducing cardiac volumes and / or reducing scar size following ischemic reperfusion injury. In some embodiments, the method comprises: administering a therapeutic composition to a subject before, during, and / or after a cardiac ischemic event, wherein the therapeutic composition comprises one or more Ang-(1-7) derivatives. The method can comprise reperfusion of ischemic cardiac tissue. There are provided, in some embodiments, methods of reducing or treating cardiac ischemic reperfusion injury. In some embodiments, the method comprises: administering a therapeutic composition to a subject during, and / or after a cardiac ischemic event, wherein the therapeutic composition comprises one or more Ang-(1-7) derivatives. The method can comprise reperfusion of ischemic cardiac tissue. Disclosed herein include methods increasing heart function, reducing mortality, reducing cardiac volumes and / or reducing scar size following ischemic reperfusion injury. In some embodiments, the method comprises: administering a therapeutic composition to a subject during and / or after a cardiac ischemic event, wherein the therapeutic composition UAZ-42224.601 UA23-296 comprises one or more Ang-(1-7) derivatives. The method can comprise reperfusion of ischemic cardiac tissue. As used herein, the term “ischemia-reperfusion injury” (IRI), shall be given its ordinary meaning, and shall also refer to tissue damage (e.g., injury) caused by ischemia, reperfusion, or ischemia followed by reperfusion. Thus, the term “ischemia-reperfusion injury” includes injuries caused by ischemia, reperfusion injuries, and injuries caused by ischemia followed by reperfusion. Myocardial infarction (MI) is a type of cardiac ischemia event that can result in IR injury of the heart tissues. As used herein, the “injury resulting from ischemia,” “injury caused by ischemia” and “ischemic injury” can refer to an injury to a cell, tissue or organ caused by ischemia, or an insufficient supply of blood (e.g., due to a blocked artery), and, thus, oxygen, resulting in damage or dysfunction of the tissue or organ. In some embodiments, the term “ischemia-reperfusion injury” refers to an injury resulting from the restoration of blood flow to an area of a tissue or organ that had previously experienced deficient blood flow due to an ischemic event. Oxidative stresses associated with reperfusion may cause damage to the affected tissues or organs. Ischemia-reperfusion injury is characterized biochemically by a depletion of oxygen during an ischemic event followed by reoxygenation and the concomitant generation of reactive oxygen species during reperfusion. In some embodiments, the compositions provided herein are administered at the time of reperfusion. “At the time of reperfusion” can range, in some embodiments, from two hours before to 2 hours after reperfusion, as well as right at the same time of reperfusion. This implies that the compositions provided herein can be administered at the same time as, for example, a thrombolytic agent is administered, or at the time of performing a surgical intervention to eliminate the clot obstructing the blood flow. There are provided, in some embodiments, methods of treating myocardial infarction. In some embodiments, the method comprises: administering a therapeutic composition to a subject during and / or after reperfusion of ischemic cardiac tissue, wherein the therapeutic composition comprises one or more Ang-(1-7) derivatives. Myocardial infarction can be a cardiac ischemic event. There are provided, in some embodiments, methods of inducing cardiomyocyte regeneration, cardiac repair, vasculogenesis and / or cardiomyocyte differentiation following a cardiac ischemic event. In some embodiments, the method comprises: administering a therapeutic composition to a subject during or after reperfusion of ischemic cardiac tissue, wherein the therapeutic composition comprises one or more Ang-(1-7) derivatives. UAZ-42224.601 UA23-296 The methods disclosed herein can comprise administrating an effective amount of at least one additional therapeutic agent or at least one additional therapy to the subject for a combination therapy. Each of the therapeutic composition and the at least one additional therapeutic agent or therapy can be administered in a separate formulation or can be administered together in a single formulation. In some embodiments, the therapeutic composition and the at least one additional therapeutic agent or therapy are administered sequentially, are administered concomitantly, and / or are administered in rotation. The at least one additional therapeutic agent or therapeutic therapy can be selected from the group consisting of Idebenone, Eplerenone, VECTTOR, AVI-4658, Ataluren / PTC124 / Translarna, BMN044 / PRO044, CAT-1004, microDystrophin AAV gene therapy (SGT-001), Galectin-1 therapy (SB-002), LTBB4 (SB-001), rAAV2.5-CMV-minidystrophin, glutamine, NFKB inhibitors, sarcoglycan, delta (35 kDa dystrophin-associated glycoprotein), insulin like growth factor-1 (IGF-1) expression, genome editing through the CRISPR / Cas9 system, any gene delivery therapy aimed at reintroducing a functional recombinant version of the dystrophin gene, Exon skipping therapeutics, read-through strategies for nonsense mutations, cell-based therapies, utrophin upregulation, myostatin inhibition, anti-inflammatories / anti- oxidants, mechanical support devices, a biologic drug, a gene therapy or therapeutic gene modulation agent, any standard therapy for muscular dystrophy, and combinations thereof. The at least one additional therapeutic agent or therapeutic therapy can be selected from the group comprising a percutaneous coronary intervention, coronary artery bypass grafting, thrombolytic therapy, anti-platelet therapy, heparin, warfarin, fibrinolytics, oxygen therapy, a vasodilator, pain medication, a beta blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB), a glycoprotein antagonist, a statin, an aldosterone antagonist, an implantable cardiac defibrillator (ICD), or any combination thereof. Reperfusion of ischemic cardiac tissue can comprise a percutaneous coronary intervention, coronary artery bypass grafting, thrombolytic therapy, anti-platelet therapy, heparin, warfarin, fibrinolytics, oxygen therapy, a vasodilator, pain medication, a beta blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB), a glycoprotein antagonist, a statin, an aldosterone antagonist, an implantable cardiac defibrillator (ICD), or any combination thereof. In some embodiments, the subject has or is suspected of having a cardiac disease. The cardiac disease can be myocardial infarction, ischemic heart disease, dilated cardiomyopathy, UAZ-42224.601 UA23-296 heart failure (e.g., congestive heart failure), ischemic cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, alcoholic cardiomyopathy, viral cardiomyopathy, tachycardia-mediated cardiomyopathy, stress-induced cardiomyopathy, amyloid cardiomyopathy, arrhythmogenic right ventricular dysplasia, left ventricular noncompaction, endocardial fibroelastosis, aortic stenosis, aortic regurgitation, mitral stenosis, mitral regurgitation, mitral prolapse, pulmonary stenosis, pulmonary regurgitation, tricuspid stenosis, tricuspid regurgitation, congenital disorder, genetic disorder, or any combination thereof. The subject can be affected by a condition selected from the group comprising alcoholic cardiomyopathy, coronary artery disease, congenital heart disease, nutritional diseases affecting the heart, ischemic cardiomyopathy, hypertensive cardiomyopathy, valvular cardiomyopathy, inflammatory cardiomyopathy, cardiomyopathy secondary to a systemic metabolic disease, dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), restrictive cardiomyopathy (RCM), noncompaction cardiomyopathy, supravalvular aortic stenosis (SVAS), vascular scarring, atherosclerosis, chronic progressive glomerular disease, glomerulosclerosis, progressive renal failure, vascular occlusion, hypertension, stenosis, diabetic retinopathy, or any combination thereof. The cardiac ischemic reperfusion injury can comprise cardiac ischemic damage, cardiac reperfusion injury, or a combination thereof. In some embodiments, the administration reduces cardiac ischemic damage, cardiac reperfusion injury, or a combination thereof, as compared to a control subject. In some embodiments, the administration reduces creatine kinase levels as compared to a control subject. The cardiac ischemic reperfusion injury can comprise injuries caused by the cardiac ischemia event, reperfusion injuries, or a combination thereof. The cardiac ischemic event can comprise one or more of myocardial infarction, coronary artery bypass grafting (CABG), cardiac bypass surgery, cardiac transplantation, and angioplasty. The cardiac ischemic event can comprise a vascular interventional procedure employing a stent, laser catheter, atherectomy catheter, angioscopy device, beta or gamma radiation catheter, rotational atherectomy device, coated stent, radioactive balloon, heatable wire, heatable balloon, biodegradable stent strut, a biodegradable sleeve, or any combination thereof. In some embodiments, the administration results in one or more of (1) increased survival as compared to a control subject, (2) improved kidney function of the subject as UAZ-42224.601 UA23-296 compared to a control subject, (3) a decrease in blood urea nitrogen (BUN) levels as compared to a control subject, (4) a reduced scarring in the left ventricle of the subject and / or improved regional wall motion in the left ventricle of the subject as compared to a control subject, (5) a decrease in end diastolic volume and / or end systolic volume as compared to a control subject, (6) an increase in ejection fraction as compared to a control subject, (7) an increase in the number of cardiomyocytes and / or mRNAs encoding proteins that are involved in differentiated cardiomyocyte muscle structure and function as compared to a control subject, (8) an increase in the mRNA levels and / or protein levels of one or more of Ank2, Kdm6a, Grk6, K1h115, Adam22, Pfkp, Gorasp2, Ralgps1, Inppl1, Kdm3a, Kit, Sort1, Dv12, Sema6d, Tead1, B4galnt2, Ltbp4, Osbp19, Nfe2I1, Tnnt2, and Fhl1 as compared to a control subject, and (9) a decrease in the mRNA levels and / or protein levels of one or more of Asph, Map6, Zfp120, Ctnndl, Eya3, Tnnt2, Kdm3a, Myo18a, Ncoa6, Slc25a13, Rpe, Ralgps1, Gimap1, Myo5a, Zeb2, Arap1, Nt5c2, Phldb1, Ttn, Camta2, Mef2c, Slk, Uimc1, Mthfd1I, Mtus1, Ythdc1, and Eif2ak4 as compared to a control subject, and (10) an increase in one of more of cardiomyocyte formation, cardiomyocyte proliferation, cardiomyocyte cell cycle activation, mitotic index of cardiomyocytes, myofilament density, borderzone wall thickness, or any combination thereof, as compared to a control subject, by at least about 1.1-fold (e.g., 1.1-fold, 1.3-fold, 1.5-fold, 1.7-fold, 1.9-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8- fold, 9-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, or a number or a range between any of these values) at a time point about 5 minutes to about 365 days after administration (e.g., about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 40 minutes, about 50 minutes, or about 60 minutes, about 1 day, about 2 days, about 4 days, about 6 days, about 8 days, about 10 days, about 20 days, about 30 days, about 40 days, about 50 days, about 60 days, about 80 days, about 100 days, about 120 days, about 140 days, about 160 days, about 180 days, about 200 days, about 220 days, about 240 days, about 260 days, about 280 days, about 300 days, about 320 days, about 340 days, about 360 days, about 365 days, or a number or a range between any of these values). In some embodiments, the administration induces endogenous cardiomyocyte regeneration. In some embodiments, the administration enhances cardiac function in the subject as compared to a control subject. Enhancing cardiac function can comprise one or more of (i) improving left ventricular function, (ii) improving fractional shortening, (iii) improving ejection fraction, (iv) reducing end-diastolic volume, (v) decreasing left ventricular mass, and (v) normalizing of heart geometry, or (vi) a combination UAZ-42224.601 UA23-296 thereof. In some embodiments, the administration has no significant effect on body weight and / or heart weight. In some embodiments, the administration does not cause one or more of arrhythmia, after contractions (AC), and contraction failure (CF). The compositions provided herein can also be used to inhibit an ischemia or ischemia- reperfusion injury to a cell, tissue or organ, ex vivo, prior to a therapeutic intervention (e.g., a tissue employed in a graft procedure, an organ employed in an organ transplant surgery). For example, prior to transplant of an organ into a host individual (e.g., during storage or transport of the organ in a sterile environment), the organ can be contacted with compositions provided herein (e.g., bathed in a solution comprising the compositions provided herein) to inhibit ischemia or ischemia-reperfusion injury. 3. Pharmaceutical Compositions While it is possible for the agents to be administered as the raw substances, it is preferable, in view of their potency, to present them as a pharmaceutical formulation. Thus, in some embodiments of the compositions disclosed herein, the composition is further formulated into a pharmaceutical formulation. The term “pharmaceutical formulation”, as used herein, refers to a composition suitable for administering to an individual that includes a pharmaceutical agent. For example, a pharmaceutical formulation according to some aspects and embodiments of the present disclosure may comprise an Ang-(1-7) derivative disclosed herein and a sterile aqueous solution. For example, the pharmaceutical formulations of the present disclosure for human use comprise the agent, together with one or more acceptable carriers therefor and optionally other therapeutic ingredients. The carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof or deleterious to the inhibitory function of the active agent. Desirably, the pharmaceutical formulations should not include oxidizing agents and other substances with which the agents are known to be incompatible. Accordingly, some embodiments disclosed herein relate to pharmaceutical formulations that include a therapeutic composition described herein and a pharmaceutically acceptable carrier. The formulations can also comprise additional ingredients such as diluents, stabilizers, excipients, and adjuvants. As used herein, “pharmaceutically acceptable” carriers, excipients, diluents, adjuvants, or stabilizers are the ones nontoxic to the cell or subject being exposed thereto (preferably inert) at the dosages and concentrations employed or that have an acceptable level of toxicity as determined by the skilled practitioner. UAZ-42224.601 UA23-296 Buffers may also be included in the pharmaceutical formulations to provide a suitable pH value for the formulation. Suitable such materials include sodium phosphate and acetate. Sodium chloride or glycerin may be used to render a formulation isotonic with the blood. If desired, the formulation may be filled into the containers under an inert atmosphere such as nitrogen or may contain an anti-oxidant, and are conveniently presented in unit dose or multi- dose form, for example, in a sealed ampoule. The carriers, diluents and adjuvants can include antioxidants such as ascorbic acid; low molecular weight polypeptides (e.g., less than about 10 residues); proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or nonionic surfactants such as Tween™, Pluronics™ or polyethylene glycol (PEG). In some embodiments, the physiologically acceptable carrier is an aqueous pH buffered solution. Generally, the pharmaceutical formulations disclosed herein can be prepared by any one of the methods and techniques known in the art. For example, solid dosage forms can be prepared by wet granulation, dry granulation, direct compression, and the like. In some embodiments, the solid dosage forms of the present disclosure may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. In some embodiments, the two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. In these instances, a variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate. Titers of the expression vector and / or one or more of the Ang-(1-7) derivatives to be administered will vary depending, for example, on the particular expression vector, the mode of administration, the treatment goal, the individual, and the cell type(s) being targeted, and can be determined by methods standard in the art. As will be readily apparent to one of ordinary skill in the art, the useful in vivo dosage of the Ang-(1-7) derivative to be administered and the particular mode of administration will UAZ-42224.601 UA23-296 vary depending upon the age, weight, the severity of the affliction, and animal species treated, the particular expression vector that is used, and the specific use for which the Ang- (1-7) derivative is employed. The determination of effective dosage levels, that is the dosage levels necessary to achieve the desired result, can be accomplished by one of ordinary skill in the art using routine pharmacological methods. Typically, human clinical applications of products are commenced at lower dosage levels, with dosage level being increased until the desired effect is achieved. Alternatively, acceptable in vitro studies can be used to establish useful doses and routes of administration of the compositions identified by the present methods using established pharmacological methods. For example, dosage regimens may be adjusted to provide the optimum desired response. For example, a single dose may be administered, or several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions and formulations in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form, as used herein, refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the present disclosure are dictated by and directly dependent on (a) the unique characteristics of the therapeutic agent and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals. Thus, the skilled artisan would appreciate, based upon the disclosure provided herein, that the dose and dosing regimen is adjusted in accordance with methods well-known in the therapeutic arts. That is, the maximum tolerable dose can be readily established, and the effective amount providing a detectable therapeutic benefit to a patient may also be determined, as can the temporal requirements for administering each agent to provide a detectable therapeutic benefit to the patient. Accordingly, while certain dose and administration regimens are exemplified herein, these examples in no way limit the dose and administration regimen that may be provided to a patient in practicing the present disclosure. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over UAZ-42224.601 UA23-296 time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and / or laboratory values. Thus, the present disclosure encompasses intra-patient dose-escalation as determined by the skilled artisan. Determining appropriate dosages and regimens for administration of therapeutic agents are well-known in the relevant art and would be understood to be encompassed by the skilled artisan once provided the teachings disclosed herein. The the Ang-(1-7) derivative disclosed herein can be administered to a subject (e.g., a human) in need thereof. The route of the administration is not particularly limited. For example, a therapeutically effective amount of the Ang-(1-7) derivative can be administered to the subject by via routes standard in the art. Non-limiting examples of the route include intramuscular, intravaginal, intravenous, intraperitoneal, subcutaneous, epicutaneous, intradermal, rectal, intraocular, pulmonary, intracranial, intraosseous, oral, buccal, or nasal. In some embodiments, the recombinant virus is administered to the subject by intramuscular injection. In some embodiments, the recombinant virus is administered to the subject by intravaginal injection. In some embodiments, the Ang-(1-7) derivative is administered to the subject by the parenteral route (e.g., by intravenous, intramuscular or subcutaneous injection), by surface scarification or by inoculation into a body cavity of the subject. In some embodiments, the Ang-(1-7) derivative is administered to muscle cells such as, cardiac muscle cells. When administering the Ang-(1-7) derivative by injection, the administration may be by continuous infusion, or by single or multiple boluses. The dosage of the administered the Ang-(1-7) derivative will vary depending upon such factors as the patient's age, weight, sex, general medical condition, and previous medical history. Typically, it is desirable to provide the recipient with a dosage of the molecule which is in the range of from about 1 μg / kg to 10 mg / kg (amount of agent / body weight of patient), although a lower or higher dosage may also be administered, In some embodiments, it may be desirable to target delivery of a therapeutic to the heart, while limiting delivery of the therapeutic to other organs. This may be accomplished by any one of a number of methods known in the art. In some embodiments, delivery to the heart UAZ-42224.601 UA23-296 of a therapeutic composition or pharmaceutical formulation described herein comprises coronary artery infusion. In certain embodiments, coronary artery infusion involves inserting a catheter through the femoral artery and passing the catheter through the aorta to the beginning of the coronary artery. In yet some other embodiments, targeted delivery of a therapeutic to the heart involves using antibody-protamine fusion proteins, such as those previously describe (Song E et al., Nature Biotechnology, 2005), to deliver the the Ang-(1-7) derivatives disclosed herein. Actual administration of the Ang-(1-7) derivative can be accomplished by using any physical method that will transport the Ang-(1-7) derivatives into the target tissue of the subject. For example, the Ang-(1-7) derivative can be injected into muscle, the bloodstream, and / or directly into the liver. Pharmaceutical formulations can be prepared as injectable formulations or as topical formulations to be delivered to the muscles by transdermal transport. For intramuscular injection, solutions in an adjuvant such as sesame or peanut oil or in aqueous propylene glycol can be employed, as well as sterile aqueous solutions. Such aqueous solutions can be buffered, if desired, and the liquid diluent first rendered isotonic with saline or glucose. Solutions of the Ang-(1-7) derivatives as a free acid (DNA contains acidic phosphate groups) or a pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxpropylcellulose. A dispersion of the Ang-(1- 7) derivatives can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The Ang-(1-7) derivative to be used can be utilized in liquid or freeze-dried form (in combination with one or more suitable preservatives and / or protective agents to protect the virus during the freeze-drying process). For gene therapy (e.g., of neurological disorders which may be ameliorated by a specific gene product) a therapeutically effective dose of the recombinant virus expressing the therapeutic protein is administered to a host in need of such treatment. The use of the Ang-(1-7) derivatives disclosed herein in the manufacture of a medicament for inducing immunity in, or providing gene therapy to, a host is within the scope of the present application. In instances where human dosages for the expression vectors and / or the Ang-(1-7) derivatives have been established for at least some condition, those same dosages, or dosages that are between about 0.1% and 500%, more preferably between about 25% and 250% of the UAZ-42224.601 UA23-296 established human dosage can be used. Where no human dosage is established, as will be the case for newly-discovered pharmaceutical formulations, a suitable human dosage can be inferred from ED50or ID50values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals A therapeutically effective amount of the Ang-(1-7) derivative can be administered to a subject at various points of time. For example, the Ang-(1-7) derivatives can be administered to the subject prior to, during, or after the infection by a virus. The Ang-(1-7) derivatives can also be administered to the subject prior to, during, or after the occurrence of a disease (e.g., cancer). Alternatively or in addition, the dosing frequency of the Ang-(1-7) derivatives can vary. For example, the Ang-(1-7) derivatives can be administered to the subject about once every week, about once every two weeks, about once every month, about one every six months, about once every year, about once every two years, about once every three years, about once every four years, about once every five years, about once every six years, about once every seven years, about once every eight years, about once every nine years, about once every ten years, or about once every fifteen years. In some embodiments, the Ang-(1-7) derivative is administered to the subject at most about once every week, at most about once every two weeks, at most about once every month, at most about one every six months, at most about once every year, at most about once every two years, at most about once every three years, at most about once every four years, at most about once every five years, at most about once every six years, at most about once every seven years, at most about once every eight years, at most about once every nine years, at most about once every ten years, or at most about once every fifteen years. In some embodiments, a pharmaceutical kit is provided, wherein the kit comprises: any of the forgoing the therapeutic compositions and pharmaceutical formulations, and written information (a) indicating that the formulation is useful for inhibiting, in myocardial cells, such as, for example cardiomyocytes, the function of a gene associated with the heart disease and / or (b) providing guidance on administration of the pharmaceutical formulation. 4. Combination Therapies In some embodiments, the therapeutic compositions and pharmaceutical formulations including the Ang-(1-7) derivatives disclosed herein can be used in combination with one or more additional therapeutic agents. In some embodiments, the therapeutic compositions and UAZ-42224.601 UA23-296 pharmaceutical formulations the Ang-(1-7) derivatives can be used in combination with one or more therapeutic therapies. Additional therapeutic agents useful for the methods of the present disclosure also include, but are not limited to, anti-platelet therapy, thrombolysis, primary angioplasty, Heparin, magnesium sulphate, Insulin, aspirin, cholesterol lowering drugs, angiotensin- receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors. In particular, ACE inhibitors have clear benefits when used to treat patients with chronic heart failure and high-risk acute myocardial infarction; this is possibly because they inhibit production of inflammatory cytokines by angiotensin II. A non-limiting listing of additional therapeutic agents and therapies includes ACE inhibitors, such as Captopril, Enalapril, Lisinopril, or Quinapril; Angiotensin II receptor blockers, such as Valsartan; Beta-blockers, such as Carvedilol, Metoprolol, and bisoprolol; Vasodilators (via NO), such as Hydralazine, Isosorbide dinitrate, and Isosorbide mononitrate; Statins, such as Simvastatin, Atrovastatin, Fluvastatin, Lovastatin, Rosuvastatin or pravastatin; Anticoagulation drugs, such as Aspirin, Warfarin, or Heparin; or Inotropic agents, such as Dobutamine, Dopamine, Milrinone, Amrinone, Nitroprusside, Nitroglycerin, or nesiritide; Cardiac Glycosides, such as Digoxin; Antiarrhythmic agents, such as Calcium channel blockers, for example, Verapamil and Diltiazem or Class III antiarrhythmic agents, for example, Amiodarone, Sotalol or, defetilide; Diuretics, such as Loop diuretics, for example, Furosemide, Bumetanide, or Torsemide, Thiazide diuretics, for example, hydrochlorothiazide, Aldosterone antagonists, for example, Spironolactone or eplerenone. Alternatively or in addition, other treatments of cardiac disease are also suitable, such as Pacemakers, Defibrillators, Mechanical circulatory support, such as Counterpulsation devices (intraaortic balloon pump or noninvasive counterpulsation), Cardiopulmonary assist devices, or Left ventricular assist devices; Surgery, such as cardiac transplantation, heart-lung transplantation, or heart-kidney transplantation; or immunosuppressive agents, such as Myocophnolate mofetil, Azathiorine, Cyclosporine, Sirolimus, Tacrolimus, Corticosteroids Antithymocyte globulin, for example, Thymoglobulin or ATGAM, OKT3, IL-2 receptor antibodies, for example, Basilliximab or Daclizumab are also suitable. In some embodiments, at least one of the additional therapeutic agents or therapies includes a biologic drug. In some embodiments, the at least one additional therapeutic agent or therapy comprises a gene therapy or therapeutic gene modulation agent. As used herein, therapeutic gene modulation refers to the practice of altering the expression of a gene at one UAZ-42224.601 UA23-296 of various stages, with a view to alleviate some form of ailment. It differs from gene therapy in that gene modulation seeks to alter the expression of an endogenous gene, for example through the introduction of a gene encoding a novel modulatory protein, whereas gene therapy concerns the introduction of a gene whose product aids the recipient directly. Modulation of gene expression can be mediated at the level of transcription by DNA-binding agents, which can be for example, artificial transcription factors, small molecules, or synthetic oligonucleotides. Alternatively or in addition, it can also be mediated post- transcriptionally through RNA interference. The therapeutic compositions, pharmaceutical formulations disclosed herein and the additional therapeutic agents or therapies can be further formulated into final pharmaceutical preparations suitable for specific intended uses. In some embodiments, the therapeutic composition and the additional therapeutic agent or therapy are administered in a single formulation. In some embodiments, each of the therapeutic composition and the additional therapeutic agent or therapy is administered in a separate formulation. In some embodiments of the methods disclosed herein, the therapeutic composition and / or the additional therapeutic agent or therapy is administered to the subject in a single dose. In some embodiments, the therapeutic composition and / or the additional therapeutic agent or therapy is administered to the subject in multiple dosages. In some embodiments, the dosages are equal to one another. In some embodiments, the dosages are different from one another. In some embodiments, the therapeutic composition and / or the additional therapeutic agent or therapy is administered to the subject in gradually increasing dosages over time. In some embodiments, the therapeutic composition and / or the additional therapeutic agent or therapy is administered in gradually decreasing dosages over time. The order of the administration of the therapeutic compositions and pharmaceutical formulations, with one or more additional therapeutic agent or therapy, can vary. In some embodiments, a therapeutic composition or pharmaceutical formulation disclosed herein can be administered prior to the administration of all additional therapeutic agent or therapy. In some embodiments, a therapeutic composition or pharmaceutical formulation disclosed herein can be administered prior to at least one additional therapeutic agent or therapy. In some embodiment, a therapeutic composition or pharmaceutical formulation disclosed herein can be administered concomitantly with one or more additional therapeutic agent or therapy. In yet still other embodiments, a therapeutic composition or pharmaceutical formulation disclosed herein can be administered subsequent to the administration of at least one UAZ-42224.601 UA23-296 additional therapeutic agent or therapy. In some embodiments, a therapeutic composition or pharmaceutical formulation disclosed herein can be administered subsequent to the administration of all additional therapeutic agent or therapy. In yet some embodiments, a therapeutic composition or pharmaceutical formulation disclosed herein and at least one additional therapeutic agent or therapy are administered in rotation (e.g., cycling therapy). For examples, in some embodiments, a therapeutic composition or pharmaceutical formulation disclosed herein and at least one additional therapeutic agent or therapy are cyclically administered to a subject. Cycling therapy involves the administration of a first active agent or therapy for a period of time, followed by the administration of a second active agent or therapy for a period of time and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more therapies, avoid or reduce the side effects of one or more therapies, and / or improve the efficacy of treatment. In some embodiments, intermittent therapy is an alternative to continuous therapy. For example, intermittent therapy can be used for a period of 6 months on, followed by a period of 6 months off. In some embodiments, one or more therapeutic agents or therapies are provided for one month on, followed by one month off. In some embodiments, one or more therapeutic agents or therapies are provided for three months on, followed by three months off. Accordingly, one or more of the therapeutic compositions or pharmaceutical formulations disclosed herein can be provided before, during and / or after administering one or more additional therapeutic agents or therapies, as described above. EXPERIMENTAL The following examples are illustrative, but not limiting, of the compounds, compositions, and methods of the present disclosure. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered in clinical therapy and which are obvious to those skilled in the art are within the spirit and scope of the disclosure. Example 1. This example describes the materials and methods utilized in Examples 2-9. Animals UAZ-42224.601 UA23-296 Experimental design: All animal use in this study conformed to the guidelines of the Institutional Animal Care and Use Committee at the University of Arizona and the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals. In previous published studies it was shown that treatment of healthy IR-Saline mice with daily injections of Ang-(1-7) and PNA5 have no negative effect on heart function or circulating cytokines[14, 16]. Male C57Bl / 6J mice, were subject to myocardial IR injury protocol at 3 months of age. Upon recovery from the IR protocol (same day), mice received daily subcutaneous injections of PNA5 (n=14) at 100µg / kg / day or saline (n=12) for 8-weeks post-IR (Figure1)

[0016]

[0017] . Control mice underwent sham surgery were treated with saline (n=5), DMSO (n=5), or PNA5 (n=6) s.c. All mice underwent transthoracic echocardiography at 2-, 5-, and 8-weeks post-IR surgery. At 8-weeks post-IR, mice also underwent a novel object recognition test (NOR) and were then sacrificed. Sham experimental timelines: Sham mice were treated with saline or PNA5 for EF% comparison: mice underwent sham surgery via left-sided thoracotomy at the fourth intercostal space.8 weeks post-surgery, mice were treated with saline or PNA5 (1.0mg / kg dissolved in saline) daily subcutaneously for 21 days. Echocardiographs were measured at baseline prior to surgery and at 4-, 8-, and 12-weeks post-surgery. Control mice used in NOR comparisons: Control mice underwent sham surgery that consisted of a left-sided thoracotomy at the fourth intercostal space. Sham mice were treated five weeks post-surgery with or DMSO (n=5) s.c. for 28 days. Surgical Procedures: An ischemia reperfusion protocol was utilized in this study. Mice were anesthetized, intubated and ventilated with 2.5% isoflurane in a mixture of air and O2. A single injection of Buprenorphine-SR (Reckitt Benckiser Healthcare) at 1mg / kg body weight is given prior to surgery. A left anterior thoracotomy was performed to expose the heart and the left coronary artery (LCA) visualized. The LCA was occluded and ligation was confirmed by observing myocardial blanching of the left ventricular anterior wall and apex and t wave elevation. Following 45 minutes of occlusion, the ligature was released restoring blood flow to previously ischemic region. [20, 21] Conventional and speckle tracking-based strain echocardiography Transthoracic echocardiography (TTE): TTE were performed 2-weeks (TTE1), 5- weeks (TTE2) and 8-weeks (TTE3) post-IR. Echocardiographs were taken on anesthetized mice (1.5-2.0% isoflurane) using the Vevo 2100 High-Resolution Imaging System (Visual UAZ-42224.601 UA23-296 Sonics, Toronto, ON, Canada) with a 25-MHz transducer. Heart rate was maintained between 450-530 beats / minute. Echocardiographic images were taken in B mode. Data were analyzed using VEVO 2100® analytic software (Visual Sonics, Toronto, ON, Canada) and Vevo Strain (Visual Sonics, Toronto, ON, Canada). Results were an average of 3 measured values per animal. Speckle tracking-based echocardiograph (STE): Strain imaging using STE of 3 cycles from the parasternal long and short axis was executed for strain analysis of the left ventricle (LV) using Vevo Strain Software (Vevo LAB 1.7.1). Strain is represented as percent fractional length change from initial length during myocardial deformation [9, 12]. Strain was calculated either in the longitudinal axis radial axis (LV cavity to LV wall) or circumferential axis (endocardial shortening); radial strain was measured from the long-axis and short axis and circumferential strain was measured from short axis at apex, mid, and base. Representative traces from the global radial and circumferential strain images with the radial / circumferential velocity line plot and heat map anel). Three-dimensional Global LV radial and circumferential strain deformation with contraction represented in orange and relaxation represented as blue. Representative segmental strain curves of 6 LV segments from radial and circumferential. LV mechanical dyssynchrony was determined from both long axis and short axis views.

[0022] .

[0023] . Dyssynchrony in long axis view was calculated as Peak Strain the highest segmental strain value (PK%), the maximum time delay to peak systolic strain (Time to Peak; ^T2P) and the standard deviation of T2P (STD T2P) between opposing wall segments (anterior / posterior) at apex, mid, and base. Short axis dyssynchrony was determined from each opposing segment as anterior and inferior free walls (anterior and posterior segments), anterior and inferior walls (anterolateral and inferolateral segments), and anterior and inferior septal walls (anteroseptal and inferoseptal segments). Infarct size determination, Histopathology and Immunofluorescence Infarct size: Upon sacrifice the LCA was re-ligated and abdominal aorta was clamped. Evans Blue (0.75%; Sigma) dye was introduced into the LV apex to distinguish area-at-risk (AAR) within the LV. The heart was immediately excised and frozen at -20°C for 20 minutes and transversely sectioned (1mm thick). Heart sections were incubated in 1% 2,3,4-triphenyltetrazoliumchloride stain (TTC; Sigma) for 30 minutes at 37 °C in a water bath to identify infarct area (white) from viable tissue (red). UAZ-42224.601 UA23-296 Picrosirius Red (PSR) staining to determine fibrosis / collagen content: Following infarct size determination, sectioned hearts were then fixed in 10% formalin overnight. Fixed hearts were dehydrated in methanol and paraffin-embedded and sectioned (5μm) for immunohistochemical analysis. Paraffin-embedded hearts were stained with Picrosirius Red

[0021] Wiegert’s hematoxylin (1% Hematoxylin and 5%EtOH) followed by PSR (1% concentrated HCl and 1.16% Ferric Chloride). Full images of each heart section were stitched from imaged taken using Lecia DMI6000, for both bright field and polarized (exposure time 125 ms) settings at 20X. Collagen content was quantified from bright field and polarized images using ImageJ; Color Threshold ImageJ function was used to determine the total tissue area and collagen area in the region of interest (ROI). ROIs were taken from infarct, superficial myocardium, and mid myocardium in each area of the left ventricle segmentation, (1- Basal Anterior, 2-Basal Anteroseptal, 3- Basal Inferoseptal, 4-Basal Inferior, 5-Basal Inferolateral, 6- Basal Anterolateral, 7-Mid Anterior, 8- Mid Anteroseptal, 9- Mid Inferoseptal, 10-Mid Inferior,11-Mid Inferolateral,12-Mid Anterolateral, 13-Apical Anterior, 14-Apical Septal,15-Apical Inferior,16-Apical Lateral, 17-Apex) (Figure 6A). Collagen inlay was measured as the area of collagen (polarized image) to the corresponding total tissue area (bright field image) in each ROI. To determine each the average collagen inlay per segment the ROI values from the infarct (if there were infarct), superficial and mid myocardium were averaged per segment. Individual infarct collagen inlay was also analyzed alone. Segments with infarcts are stated in the PSR table (Table 2). Table 2. Summary of conventional transthoracic echocardiography parameters. Values are represented as ± SEM (n=12-13 for each group). A 2-way repeated measures ANOVA followed by multiple comparisons to determine differences among each experimental group and timepoint. P values of <0.05 were considered statistically significant. Ejection fraction- EF, fractional shortening- FS, end-diastolic volume- EDV, end-systolic volume- ESV. TTE1 TTE2 TTE3 e 8 99 UAZ-42224.601 UA23-296 ESV 31.1 ± 1.0 33.7 ± 1.9 0.9413 28.5 ± 1.5 25.0 ± 2.7 0.8408 25.1 ± 1.9 29.3 ± ) 2. 0.6962 (µL 6 were stained with TNF^ (17590-1AP, Proteintech, Rosemont, IL) (Rabbit, IgG 1:100), or HIF1α. 5μm thick heart sections were stained with TNF^ (17590-1AP, Proteintech, Rosemont, IL) (Rabbit, IgG 1:100) overnight at 4°C on a shaker. The following day, sections were incubated in Anti-rabbit IgG, HRP-linked Antibody (1:200) (#7074, Cell Signaling, Danvers, MA) for 2 hours at room temperature. The staining was amplified via TSA amplification at room temperature for 10 minutes via CF®647 Tyramide (Ex / Em 650 / 665 nm, #96022, Biotium, Fremont, CA). Nuclei were stained for 1 minute at 1:300 with DAPI (ThermoFisher cat.62248). Slides were imaged at10x (TNFα, Cy5, 400ms exposure time; DAPI, 20ms exposure time) and stitched using the Leica DMI6000 scope and software. Mean fluorescent intensity was determined using ImageJ. Novel Object Recognition (NOR) Test Mice cognition was measured using a novel object recognition test (NOR) test as described previously [14-16]. There were no differences between groups for familiarization phase indicating that exploration was not impaired between groups. Mice cognition was measured using a novel object recognition test (NOR) test as described previously [2, 17-19]. A brief description: for two days mice were habituated to the testing arena, for 10 minutes per day. The learning phase follows habituation on the third day. During the learning phase, two identical objects are able to be explored for 6 minutes within the testing arena. Mice were returned to their home cages for two hours at the end of the learning phase. Following the two-hour period, mice were placed again into the testing arena for the memory testing phase. During the memory phase a novel object replaces one of the two identical objects. For two minutes mice were allowed to explore both the objects during the testing phase. To prevent olfactory cues between testing phases and animals, the testing arena and objects were cleaned with 70% ethanol. Analysis: to score the mice recognition memory we calculate a discriminatory ratio (Discrimination ratio) by: Discrimination ratio= time spent exploring the novel object(tnovel)minus time spent exploring the familiar object (tfamiliar) divided by the total exploration time [2, 18]: UAZ-42224.601 UA23-296 Equation 1 Discrimination ratio= (tnovel- tfamiliar) / (total exploration time) A positive Discrimination ratio is a result of a mouse interacting more with the novel object than the familiar object. Whie a negative Discrimination ratio is a result of mice spending more time with the familiar object than the novel object. Statistics GraphPad Prism was used to analyze data and values are represented as mean ± SEM. All data sets were tested for normal Gaussian distribution. Shapiro-Wilk test as it is an appropriate test for group sizes smaller than 50. To determine the impact of the IR protocol with or without PNA5 treatment over time, a 2-way repeated measures ANOVA was employed followed by multiple comparisons to determine differences among each experimental group and timepoint. The association between GLS, inflammation, TNFα, and fibrosis were analyzed using simple linear regression. The best-fit line for correlations was generated via linear regression and Pearson's correlation. All measurements were executed by blinded observers including echocardiography, histopathology, and immunofluorescence. Each biological sample included the averaged values of all technical replicates. Example 2. This example demonstrated that PNA5 improved Ejection Fraction post-IR. Conventional trans-thoracic echocardiography (TTE) was performed at 2 (TTE1), 5 (TTE2), and 8 (TTE3) weeks post-IR to longitudinally track the impact of PNA5 treatment on cardiac function and morphology post-IR. There was a significant impact treatment on EF% (p=0.022) and EF% progression (*p=0.039) by a repeated measures 2-way ANOVA (Figure 1, Table 2). As expected, subjecting mice to the IR protocol significantly decreased EF% in both saline-treated and PNA5-treated groups when analyzed 2 weeks post-IR surgery (TTE1) compared to Sham controls (Figure 2, Table 2). Sham controls included Saline- treated and PNA5-treated for up to 12 weeks and demonstrated no impact of long-term PNA5 administration as previously shown in Ang(1-7)-treated mice [15, 16, 24]. By 5 weeks post- IR (TTE2), EF% of PNA5-treated animals recovered to sham levels and was significantly improved from 2-week EF% levels (TTE2) measured in Saline-treated or PNA5-treated mice (Figure 1). At 8 weeks post-IR, PNA5-treated mice maintained EF% levels that were not UAZ-42224.601 UA23-296 significantly different from 5-week EF% but also not different from 2-week levels or sham levels. Furthermore, EF% in PNA5-treated mice at 8 weeks was not significantly different from EF% in Saline-treated mice at 8 weeks. Saline-treated EF% remained significantly less post-IR from Sham controls and unchanged over the 8-week treatment protocol. EDV at 2 weeks was significantly (p=0.0379) less at 5 weeks (TTE2) post-IR in the PNA5-treated group (Figure 1B). End-systolic volume (ESV), on the other hand, significantly improved (**p=0.0045) over the experimental protocol, which occurred more rapidly in the PNA5- treated group (**p=0.0084 at 5 weeks, TTE2) than in Saline (**p=0.0080 at 8 weeks, TTE3) (Figure 1C). Although early revascularization after MI is the most effective therapeutic strategy, the data suggests conventional TTE may be insufficient to fully evaluate the impact of therapeutic intervention such as PNA5 post-MI. Example 3. This example demonstrates that PNA5 improved global longitudinal strain. As mentioned above, STE-based strain imaging and analysis may improve the sensitivity and specificity of how PNA5 treatment impacts IR injury. Myocardial deformation in the longitudinal plane reflects functional shortening of endocardial fibers. Global longitudinal strain (GLS) reflects myocardial deformation of endocardial fibers in the longitudinal plane and is an early indicator of cardiac dysfunction especially following MI [13, 25]. Similar to EF%, subjecting mice to the IR protocol significantly increased (worsened) GLS in both saline-treated and PNA5-treated groups when analyzed 2 weeks post-IR surgery (TTE1) compared to Sham controls (Figure 3). There was a significant impact of PNA5 (**p=0.0017) on GLS that also improved over the experimental time course (***p=0.0007) (Figure 1D). By 5 weeks post-IR (TTE2), PNA5 significantly improved (**p=0.0047) GLS over the 2-week GLS (TTE1) and compared to Saline-treated animals (***p=0.0009). While GLS measured in PNA5-treated animals at 8 weeks (TTE3) remained significantly (*p=0.0118) improved over GLS at 2 weeks (TTE1) and compared to Saline- treated at 8 weeks (**p=0.0055), Saline-treated animals showed beneficial signs of cardiac remodeling with an 8-week (TTE3) GLS that was significantly improved (*p=0.0313) from 2 weeks (TTE1). Left coronary ligation instigating the MI predominantly impacts perfusion to the anterior myocardium. Accordingly, the highest strain value or Peak Strain (PK%) at both the anterior and posterior basal myocardium were calculated. PK% showed a similar pattern as UAZ-42224.601 UA23-296 GLS (Figure 1E) with important regional differences. There was a significant impact of PNA5 treatment on PK% at the base whether measured at the anterior (*p=0.0174) or posterior (**p=0.0056) region. Anterior PK% (Figure 1F) measured at the base showed a significant improvement (*p=0.0497) in the PNA5- compared to Saline-treated group by 5 weeks post-IR (TTE2). The posterior myocardium, however, showed a significant benefit (**p=0.0056) with PNA5 treatment that also improved over time (**p=0.0079). This improvement in PK% with PNA5 was evident by 5 weeks post-MI (Saline vs PNA5 at TTE2; *p=0.0130) and 8 weeks (TTE3 vs TTE1; *p=0.0465). The posterior myocardium in Saline- treated animals showed delayed recovery of PK%, which demonstrated significance at 8 weeks (TTE3) when compared to 2 weeks (TTE1; **p=0.0085) and 5 weeks (TTE2; *p=0.0406). Similar T2P trends were measured in the posterior mid-wall, posterior apex wall, and the anterior apex wall where T2P on the LV long axis was significantly higher in the PNA5-treated mice 5-weeks post-IR compared to Saline-treated mice (Figure 3C-D). Similarly, PNA5-treated mice had significantly higher T2P compared to Saline-treated mice 8-weeks post-IR at the anterior mid-wall (Figure 4A). These data suggest that PNA5 not only prevented worsening strain but promoted improved heart wall movement on the longitudinal axis. Example 4. This example demonstrates that PNA5 reversed LV dyssynchrony. Longitudinal dyssynchrony: Global and regional differences in longitudinal dyssynchrony were measured. Strain dyssynchrony is measured from the strain velocity line plots (Figure 5) determined from each segment (Figure 5) as described in the Methods section. PNA5 significantly reduced (*p=0.0416) global longitudinal dyssynchrony 8 weeks (TTE3) post-IR compared to Saline-treated mice (Figure 5A). The most prominent improvement of PNA5 was seen at the base where PNA5 treatment had a significant (**p=0.0071) impact by week 5 (TTE2; *p=0.0164) compared to Saline that continued through week 8 (TTE3; *p=0.0290) (Figure 5B). These results indicate that PNA5 can improve longitudinal uniformity during systole in following IR injury. Radial dyssynchrony (Long Axis): Because radial strain was measured from both the long-axis and short-axis, radial dyssynchrony was determined from both parasternal long and short-axis views. Radial dyssynchrony in the long axis revealed a significant treatment effect (**p=0.0040) that persisted over time (*p=0.0418) (Figure 6A). The impact of PNA5 UAZ-42224.601 UA23-296 treatment on radial dyssynchrony also depended on the specific time of measurement, as evidenced by a significant interaction between treatment over time (*p=0.0122). These differences were driven by a significant (worsening) increase (**p=0.0033) in radial dyssynchrony in Saline-treated compared to PNA5-treated mice at 8 weeks (TTE3) and compared to Saline-treated (**p=0.0054) at 5 weeks (TTE2). Radial dyssynchrony calculated as the standard deviation of T2P (STD T2P) was impacted (*p=0.0164) by treatment over the time course of the protocol where Saline-treated mice showed worsening dyssynchrony by 8 weeks (TTE3; **p=0.0048) (Figure 6B). Radial dyssynchrony in Saline-treated mice from the mid-axis view demonstrated significant worsening by 8 weeks post-IR (*p=0.0459) most likely reparative remodeling in the infarct area of PNA5-treated mice (Figure 6C). Radial dyssynchrony at the apex showed a more complex phenotype but still indicative of a beneficial impact following PNA5 treatment (Figure 6D). PNA5 significantly impacted (*p=0.0128) radial dyssynchrony at the apex which also showed significant interaction (**p=0.0025) over time. By 8 weeks post-MI, radial dyssynchrony at the apex worsened in Saline-treated but improved in PNA5-treated mice. This was illustrated by the following significant differences: Saline vs PNA5 at TT3 (****p<0.0001); Saline at TTE1 vs TTE3 (*p=0.0257); PNA5 at TTE3 vs TTE1 (**p=0.0055) and TTE2 (*p=0.0223). Radial and Circumferential dyssynchrony (Short Axis): Radial and circumferential dyssynchrony assessed from the parasternal short-axis measures myocardial thickening (radial) and shortening (circumferential) and are prognostic indicators of myocardial and LV recovery and remodeling post-MI

[0026] . Similar to the long-axis measures of radial dyssynchrony, PNA5-treated mice either attenuated or improved systolic synchronization post-MI. Specifically, PNA5 treatment significantly impacted radial dyssynchrony measured in the short-axis (at the MID-region) determined by the time-delay to peak strain (^T2P; **p=0.0016) marked by a significant difference (*p=0.0142) between Saline and PNA5 at TTE2 (Figure 7A) or standard deviation (*p=0.0176) marked by a significant difference(**p=0.0023) between Saline and PNA5 at TTE3 (Figure 7B). Measured radial dyssynchrony at the MID Free Wall (Figure 7C) and BASE Septal (Figure 7D) regions also indicated a beneficial impact of PNA5 treatment post-MI (***p=0.0006 and ***p=0.0003, respectively). Interestingly, the MID Free Wall identified an early benefit of PNA5-treatment with significant improvements over Saline at week 2 (TTE1; *p=0.0272) and week 5 (TTE2; ***p=0.0008) which normalized by week 8 (TTE3). Septal dyssynchrony at the base, on the UAZ-42224.601 UA23-296 other hand, illustrated a benefit of PNA5 treatment over Saline at week 5 (TTE2; *p=0.0440) and week 8 (TTE3; **p=0.0018) but not week 2 (TTE1). Although radial dyssynchrony is better correlated with LV remodeling post-MI, circumferential dyssynchrony may better predict regional wall shortening dyssynchrony as a reflection of circumferentially-oriented fibers in the myocardium. Circumferential dyssynchrony at the BASE was significantly impacted by PNA5 treatment measured by time- delay to peak strain (^T2P; **p=0.0011) (Figure 8A) driven by a significant difference between Saline and PNA5 at TTE2 (*p=0.0254) and TTE3 (*p=0.0462) or STD T2P (**p=0.0081) driven by a significant difference between Saline and PNA5 at TTE2 (**p=0.0035) and PNA5 treatment (*p=0.0113) at 2 weeks (TTE1) compared to 5 weeks (TTE2) (Figure 8B). Circumferential dyssynchrony at the Free Wall (BASE) was also preserved by PNA5 treatment (*p=0.0120) and a specific difference between Saline- and PNA5-treated mice at 8 weeks (TTE3; *p=0.0215) (Figure 8C). Considering the location and size of the infarct, the impact of PNA5 treatment on circumferential dyssynchrony measured at the MID-region of the myocardium was segment- dependent. Circumferential dyssynchrony (MID) measured by ^T2P was dependent on both treatment and time with a significant interaction (*p=0.0461) indicated by attenuation of dyssynchrony in PNA5- compared to Saline-treated at 5 weeks (TTE2; **p=0.0031) that appeared to normalize by 8 weeks (TTE2 vs TTE2; *p=0.0260) (Figure 8D). However, dyssynchrony by STD T2P was treatment-dependent (*p=0.0166) with a significant difference (**p=0.0029) between PNA5- and Saline-treated by 5 weeks (TTE2) (Figure 8E). Differences in circumferential dyssynchrony at the apex was limited to the septal region (Figure 8H-J). PNA5 treatment resulted in significant differences in septal circumferential dyssynchrony in the MID (**p=0.0030; Figure 8F) and APEX (*p=0.0155; Figure 8J). Specifically, PNA5 attenuated MID-Septal circumferential dyssynchrony 5 weeks (TTE2) post-MI (Saline vs PNA5; *p=0.0104) that appeared to worsen by 8 weeks with PNA5 treatment (TTE1 vs TTE3; *p=0.0443). Septal circumferential dyssynchrony at the APEX showed a significant interaction (*p=0.0422) between PNA5 treatment over time where PNA5-treated mice demonstrated significant improvement (**p=0.0023) by 8 weeks (TTE3) post-MI. Example 5. This example demonstrates that PNA5 improved cardiac outcomes post-MI. UAZ-42224.601 UA23-296 PNA5 attenuated infarct size: STE-based strain imaging measures myocardial deformation along multiple axes permitting temporal and spatial evaluation of a myocardial infarction. Strain analysis coupled with calculations of dyssynchrony indicates PNA5 treatment impacted the size, function and location of cardiac injury post-IR. Ligation of the left coronary artery was confirmed by visual blanching starting from the occlusion site to the apex of the anterior myocardium as described in the Methods sections. Following sacrifice, hearts were excised and absolute infarct size was determined as percentage of the entire LV indicated by the staining and histology (Figure 9; top panel). At 8-weeks post-IR, PNA5 treatment significantly (*p=0.0111) decreased infarct area by 33.0+ / -8.4% compared to the Saline-treated mice (Figure 9A). When infarct size was normalized to total LV area, the impact of PNA5 treatment was amplified where PNA5-treated hearts showed a significant (**p=0.0036) decrease in infarct area normalized to total LV by 39.7 + / -8.9% compared to Saline-treated animals (Figure 9B). There was no impact of PNA5 on total LV area (Figure 9C). PNA5 decreased IR-related fibrosis: To quantify further morphological change, fibrosis of the left ventricle was measured using PSR staining. PNA5 decreased IR-related collagen inlay throughout the anterior and anterolateral areas of the heart. Bullseye plots of the mean percentage of collagen inlay depict a decrease in fibrosis within the PNA5-treated heart compared to the IR-Saline primarily localized in segments that follow the infarct area of an occluded LAD. The bullseye represents the mean collagen % inlay, where red has the highest percentage of collagen with a max of 40%, white represents 20 percent collagen inlay, and blue represents 0 collagen inlay. Fibrosis appears to have increased towards the base of the heart with the greater amount around the infarct zones (the anterior and anterolateral wall). PNA5 decreased collagen inlay with a greater occurrence closer to the apex of the heart. However, collagen prevalence in the infarct area was significantly decreased through the heart’s base, mid, and apical segments. Specifically, there is a significant decrease in percentage of collagen in the basal anterolateral, mid anterior, apical, anterior, apical inferior, apical lateral, and apex segments of the heart. Table 3. Values for left ventricular segment collagen content. Values are represented as ± SEM (n=12-13 for each group). Percent collagen content was the collagen pixel area relative to the segment pixel area. The inset illustrated in grey was the collagen pixel area relative as a fraction of identifiable infarct within each segment. Values are represented as ± SEM (n=12- UAZ-42224.601 UA23-296 13 for each group). T-tests were used to compare PNA5 and Saline groups; P values of <0.05 were considered statistically significant. Segment Saline PNA5 P Value 9 * * * * * * Example 6. This example demonstrates that PNA5 decreased IR-related inflammation in heart tissue. PNA5 significantly decreased TNFα (red) expression within the infarct areas of ischemic reperfusion injured hearts (Figure 10A, 4D). Additionally, PNA5 significantly decreased ratios of TNFα expression in the infarct compared to the entire heart and LV (Figure 10B, 4C). These results suggest that PNA5 decreased inflammation in infarct areas. PNA5 significantly decreased HIF1α at the infarct area hearts 8 weeks post IR (Figure 11B, 5C-F). There was no change in HIF1α in other regions of the heart including border distal areas from the infarct (Figure 11A, 5C-F). These results suggest that PNA5 decreased HIF1α in infarct areas. UAZ-42224.601 UA23-296 Example 7. This example demonstrates that global longitudinal strain correlated with infarct size and inflammation. In efforts to gain insight on how PNA5 improved GLS post-IR, values of infarct size and TNFα mean fluorescent intensity to GLS values were calculated. Global longitudinal strain significantly positively correlated with both infarct size and ratio of inflammation in the infarct area to the entire heart 8-weeks post-IR (Figure 12A, 6B). Indicating that as infarct size and inflammation increases, GLS worsens. Additionally, there is a significant and positive correlation between TNFα mean intensity and LV heart collagen content. Suggesting that as inflammation increases, an increase in LV collagen content was seen (Figure 12C). Example 8. This example demonstrates that PNA5 protects memory impairment post-MI. When compared to mice that underwent sham surgeries, IR-Saline treated mice has significantly decreased discrimination ratio indicating cognitive impairment. These results suggest that IR injury can negatively impact memory. Further, it was observed that PNA5 protects against cognitive decline in IR mice as IR-PNA5-treated mice have a significantly higher Discrimination ratio than IR-Saline mice. Example 9. This example provides a discussion pertaining to Examples 1-8. In total, the greatest difference between treatment groups dyssynchrony are found in regions bordering the infarct such as the free wall at the base and the septal wall at the apex. These results indicate that PNA5 potentially had the greatest effect in circular dyssynchrony in the border regions close to the infarct than regions with infarct. While reperfusion therapies are essential to address myocardial ischemic infarct the repercussions of reperfusion results in additional injury to the myocardium. Progression of scar tissue and additional reperfusion injury are sequelae to IRI sought to be ameliorated to improve mortality rates and maintain heart function. Examples 1-8 show that PNA5 improves infarct size, inflammation, fibrosis, and heart function within IRI mice. On further investigation, it was determined that PNA5 improves global longitudinal strain and prevents worsened dyssynchrony on bordering regions of the UAZ-42224.601 UA23-296 left ventricle. These results suggest that PNA5 may be a potential therapeutic treatment for immediate delivery upon a myocardial ischemic event to lessen the development of IRI. Additionally, as PNA5 is a glycosylated form of Ang-(1-7), this study provides potential effect of Ang-(1-7) on heart functional response in terms of strain following IR. Strain analysis on Ang-(1-7) in IRI is limited and could provide potential methods to further assess what location the treatment is targeting. Further, the abilities of PNA5 to address early cardiac dysfunction, thereby preventing / slowing the disease progression towards HF were shown. Following ischemic events, necrosis, and apoptosis of the myocardium there is an inflammatory response and activation of fibroblasts [1, 8]. Upon reperfusion, there is an increase in ROS, intracellular calcium overload, and mitochondrial damage which promotes apoptosis and further inflammatory activity. Myocardial loss and fibrosis can lead to the development of cardiac dysfunction and impaired contractile function. PNA5 is an ideal therapeutic to treat IR as it has the ability to decrease ROS, inhibit proinflammatory cytokine production, inhibit fibrosis, and promote vasodilation [14-16]. Further it has a longer half-life than Ang-(1-7). PNA5 improves infarcts size The examples described herein have demonstrated that treatments with PNA5 immediately upon reperfusion of MI significantly decreases infarct size 8-weeks post-IR. A limited number of studies have previously shown that Ang-(1-7) significantly reduces infarct size of the schematic reperfusion injuries via MasR activation

[0027] . Akhtar et al. proposed that the decrease in infarct size is likely due to a decrease in inflammation and ROS as a result of Ang-(1-7) MasR activation. Other studies have also shown that the cardioprotective mechanisms of Ang-(1-7) may also be a result of restoring intracellular calcium homeostasis and potentially by activating AKT thereby inhibiting autophagy and apoptosis

[0028] . PNA5 works via the MasR

[0016] , and thus is likely to decrease infarct size in IRI through the same mechanisms as Ang-(1-7), via decreased inflammation, ROS, and fibrosis [14, 19, 28-30]. The limited number of studies that demonstrate a decrease in infarct size post-ischemic reperfusion using Ang-(1-7) treatments or Ang-(1-7) derivative drugs speak to the impact of the study, and the novelty of PNA5 treatments to reduce infarct size in IRI. PNA5 prevents IRI-related fibrosis UAZ-42224.601 UA23-296 It was demonstrated that PNA5 significantly reduces fibrosis within the left ventricle, measured by PSR. The main areas that had a significant decrease in fibrosis from PNA5 treatments are those both at the area of infarct and immediately bordering the infarct. Previous studies have shown the cardioprotective effects of Ang-(1-7) to prevent fibrosis and several CVD including angiotensin-II (Ang-II) dependent hypertension [30, 31] and MI [17, 32]. Fibrosis has been shown to impede cardiac function as increases in collagen deposition increases wall stiffness and can affect both relaxation and contractility[8, 33]. PNA5 prevents inflammation in infarcted areas of the heart It was shown that PNA5 significantly decreases inflammation within IRI hearts specifically in the infarct area. Previous studies have shown that in Ang-II-dependent hypertension in ratstreated with Ang-(1-7), activation of MasR prevents inflammatory cell infiltrate, as Ang-(1-7) administration significantly decreased CD64

[0030] . Other studies have shown that Ang-(1-7) decreases levels of proinflammatory cytokines including TNFα, and IL-6 in rats with MI [19, 34]. Inflammatory pathways have been shown to contribute to increased collagen deposition in part by activation of fibroblasts and myofibroblasts

[0035] . These findings are similar to previously shown results that TNFα positively correlates with an increase in percent collagen inlay in the left ventricle. Hence, decreases in inflammation may result in less fibrosis and potentially better heart function. Additionally, linear regression shows that an TNFα (normalized to LV mean intensity) is significantly positively correlated to GLS. As TNFα increases the GLS value also increases. Increases in GSL values is representative of worsened heart function as the heart has less movement of the apex towards the base during systole

[0012] . These results suggest that IR-PNA5-treated mice have improved heart function than IR-Saline-treated mice potentially through decreasing inflammation. PNA5 mitigated IR-associated deterioration in cardiac function: It was demonstrated that IR-PNA5-treated mice have better cardiac function at 5- weeks post-IR as EF increases compared to IR-Saline-treated mice at 5-weeks post-IR. Previous studies have shown that in mice with MI treated with Olmesartan, which increases Ang-(1-7) and ACEII activity, EF is significantly increased compared to control MI mice

[0017] . Additionally, it appears that PNA5 not only maintains but improves EF at 5-weeks post- IR as it is significantly increased from the previous EF measurements 2-weeks post-IR. However, these significances do not appear to persist when looking at these more general UAZ-42224.601 UA23-296 echocardiographic parameters that tend to be less sensitive. Because a persistent decrease in inflammation and fibrosis 8-weeks post-IR was seen, it would be likely that there are improvements in heart function still 8-weeks post-IR. Especially because previous studies have demonstrated that both inflammation and collagen deposition can contribute to worsened heart function, it was believed that more specific regional analysis of heart function were needed. To explore heart function more in depth echo strain via 2DST was studied. In fact, it was found that PNA5 impacts heart function through the 8-weeks post-IR, as GLS was significantly improved with PNA5 at both 5- weeks and 8-weeks post-IR. Further in-depth analysis revealed the largest improvement in peak strain (PK%) is located at the base. It is possible that EF did not reflect these differences as it is a measurement of the entire heart function thereby missing impairments seen in regional areas. Previous studies have shown GLS to be a more sensitive prognostic factor than left ventricular EF for predicting clinical outcomes and remodeling in patients with acute MIs

[0011] . Additionally, a potential contributor to the changes to EF only being observed at 5-weeks post-IRI could be the significant increase in T2P observed at 5-weeks post-IR. As mentioned previously T2P on its own is susceptible to change based on HR which can be influenced by animal anesthetization

[0036] . A previous study by Berli et al. found that strain rate and strain T2P were decreased in anesthetized goats than in non-anesthetized goats. However, they also determined that strain analysis especially on the long axis 2DST was still a valid method to characterize heart function even during anesthetization. Additionally, the global longitudinal strain also served as confirmation to an ischemic reperfusion model as previous papers that tested GLS strain to verify IR showed that in failed IR there is a gradual improvement 1 to 42 days (6 weeks) post ischemic reperfusion injury in global longitudinal strain[1]. Whereas mice with successful IR, with 45 minutes of ischemia maintained a GLS of about 10 %. The GLS remained around 15% for over 42 days, indicating a successful IR model. Similarly, Yang et.al. also states similar trends with EF in successful IR mice; IR mice maintained a decreased ejection fraction of ~40% similar to the saline-treated IR mice. It was further shown that PNA5 improves synchrony on all three axis of movement, Longitudinal, radial, and circumferential post-IR. At 5-weeks post-IR, PNA5 decreases dyssynchrony for longitudinal, radial base (short axis), and circumferential base and mid strain. At 5-weeks post-IR, PNA5’s main effects appear to occur primarily at the base in regionspotentially bordering the infarct area. At 8-weeks post-IR, PNA5’s effects are most UAZ-42224.601 UA23-296 observed in the base of longitudinal strain, apex and mid regions of the radial strain (on the long-axis), and the base and apex regions in the circumferential strain. PNA5 decreases asynchrony 5-weeks post-IR at the base region of the heart. Later, at 8-weeks post-IR, PNA5 decreases asynchrony in circumferential strain in the mid-region of the heart. These results suggest that PNA5 addresses morphological changes in IR heart in different areas as progression of damage and repair ensue following the initial ischemic refusion event. PNA5 protects memory impairment in mice with ischemic reperfusion injury Lastly, the described results demonstrate that PNA5 protects against cognitive impairment in IR. IR-Saline-treated mice had significantly decreased discrimination ratio compared to sham mice treated with DMSO. These results support that cardiac damage can promote cognitive impairment. Previous studies have also shown that mice with IR have impaired cognitive function

[0037] . Further, an established model for vascular contributions to cognitive impairment and dementia induced by HF exists [14-16, 38]. Moreover, it was shown that PNA5 protects from cognitive impairment in mice with IR. The previous work demonstrated that PNA5 rescues cognitive impairment in HF [15, 16]. These results further highlight the beneficial application of PNA5 treatment immediately following an acute MI event. Having now fully described the compounds, compositions, the methods herein, it will be understood by those of skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations, and other parameters without affecting the scope of the methods, compounds, and compositions provided herein or any embodiment thereof. All patents, patent applications, and publications cited herein are fully incorporated by reference herein in their entirety. INCORPORATION BY REFERENCE The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes. The following references are herein incorporated by reference in their entireties: 1. Yang, Y., et al., Postsurgery echocardiography can predict the amount of ischemia- reperfusion injury and the resultant scar size. American Journal of Physiology-Heart and Circulatory Physiology, 2021.320(2): p. H690-H698. UAZ-42224.601 UA23-296 2. Rich, M.W., Epidemiology, clinical features, and prognosis of acute myocardial infarction in the elderly. Am J Geriatr Cardiol, 2006.15(1): p.7-11; quiz 12. 3. Tavazzi, L., Clinical epidemiology of acute myocardial infarction. Am Heart J, 1999. 138(2 Pt 2): p. S48-54. 4. Lloyd-Jones, D., et al., Heart disease and stroke statistics--2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation, 2009.119(3): p. e21-181. 5. O'Neill, W., et al., A prospective randomized clinical trial of intracoronary streptokinase versus coronary angioplasty for acute myocardial infarction. N Engl J Med, 1986.314(13): p.812-8. 6. Hausenloy, D.J. and D.M. Yellon, Myocardial ischemia-reperfusion injury: a neglected therapeutic target. Journal of Clinical Investigation, 2013.123(1): p.92-100. 7. Neri, M., et al., Ischemia / Reperfusion Injury following Acute Myocardial Infarction: A Critical Issue for Clinicians and Forensic Pathologists. Mediators of Inflammation, 2017. 2017: p.1-14. 8. Schirone, L., et al., An Overview of the Molecular Mechanisms Associated with Myocardial Ischemic Injury: State of the Art and Translational Perspectives. Cells, 2022. 11(7): p.1165. 9. Johnson, C., et al., Practical tips and tricks in measuring strain, strain rate and twist for the left and right ventricles. Echo Research and Practice, 2019.6(3): p. R87-R98. 10. Duncan, A.E., et al., Perioperative Assessment of Myocardial Deformation. Anesthesia & Analgesia, 2014.118(3): p.525-544. 11. Otterstad, J.E., et al., Prognostic impact of non-improvement of global longitudinal strain in patients with revascularized acute myocardial infarction. The International Journal of Cardiovascular Imaging, 2021.37(12): p.3477-3487. 12. Lopez-Candales, A. and D.F. Hernandez-Suarez, Strain Imaging Echocardiography: What Imaging Cardiologists Should Know. Curr Cardiol Rev, 2017.13(2): p.118-129 doi: 10 2174 / 1573403X12666161028122649. 13. Hoit, B.D., Strain and Strain Rate Echocardiography and Coronary Artery Disease. Circulation: Cardiovascular Imaging, 2011.4(2): p.179-190. 14. Hay, M., et al., Cognitive impairment in heart failure: A protective role for angiotensin- (1-7). Behav Neurosci, 2017.131(1): p.99-114. UAZ-42224.601 UA23-296 15. Hoyer-Kimura, C., et al., Neurofilament light: a possible prognostic biomarker for treatment of vascular contributions to cognitive impairment and dementia. Journal of Neuroinflammation, 2021.18(1). 16. Hay, M., et al., A Novel Angiotensin-(1-7) Glycosylated Mas Receptor Agonist for Treating Vascular Cognitive Impairment and Inflammation-Related Memory Dysfunction. Journal of Pharmacology and Experimental Therapeutics, 2019.369(1): p.9-25. 17. Wang, J., et al., The ACE2-Ang (1–7)-Mas receptor axis attenuates cardiac remodeling and fibrosis in post-myocardial infarction. Molecular Medicine Reports, 2017.16(2): p. 1973-1981. 18. Tyrankiewicz, U., et al., Activation pattern of ACE2 / Ang-(1–7) and ACE / Ang II pathway in course of heart failure assessed by multiparametric MRI in vivo in Tgαq*44 mice. Journal of Applied Physiology, 2018.124(1): p.52-65. 19. Mckinney, A., Clare, et al., Angiotensin-(1–7) and angiotensin-(1–9): function in cardiac and vascular remodelling. Clinical Science, 2014.126(12): p.815-827. 20. Danilo, C.A., et al., Bifidobacterium animalis subsp. lactis 420 mitigates the pathological impact of myocardial infarction in the mouse. Beneficial Microbes, 2017.8(2): p.257-269. 21. Konhilas, J.P., et al., Using 4-vinylcyclohexene diepoxide as a model of menopause for cardiovascular disease. Am J Physiol Heart Circ Physiol, 2020.318(6): p. H1461-h1473. 22. Helm, R.H., et al., Cardiac Dyssynchrony Analysis Using Circumferential Versus Longitudinal Strain. Circulation, 2005.111(21): p.2760-2767. 23. Cheng, A., R.H. Helm, and T.P. Abraham, Pathophysiological mechanisms underlying ventricular dyssynchrony. EP Europace, 2009.11(suppl_5): p. v10-v14. 24. Hoyer‐Kimura, C., et al., Angiotensin‐(1‐7) / Mas receptor agonist: a disease modifying therapeutic for VCID protects cognitive function and inhibits serum neurofilament light protein. Alzheimer's & Dementia, 2022.18(S10). 25. Lehner, C., et al., Oxidative Stress and Blood–Brain Barrier Dysfunction Under Particular Consideration of Matrix Metalloproteinases. Antioxidants & Redox Signaling, 2011.15(5): p.1305-1323. 26. Mollema, S.A., et al., Left ventricular dyssynchrony acutely after myocardial infarction predicts left ventricular remodeling. J Am Coll Cardiol, 2007.50(16): p.1532-40. 27. Pachauri, P., et al., Angiotensin (1–7) facilitates cardioprotection of ischemic preconditioning on ischemia–reperfusion-challenged rat heart. Molecular and Cellular Biochemistry, 2017.430(1-2): p.99-113. UAZ-42224.601 UA23-296 28. Xie, J.X., et al., The function of the ACE2 / Ang(1-7) / Mas receptor axis of the renin- angiotensin system in myocardial ischemia reperfusion injury. Eur Rev Med Pharmacol Sci, 2022.26(6): p.1852-1859. 29. Akhtar, S., et al., Mitigating Cardiotoxicity of Dendrimers: Angiotensin-(1-7) via Its Mas Receptor Ameliorates PAMAM-Induced Cardiac Dysfunction in the Isolated Mammalian Heart. Pharmaceutics, 2022.14(12): p.2673. 30. Castoldi, G., et al., Angiotensin Type 2 and Mas Receptor Activation Prevents Myocardial Fibrosis and Hypertrophy through the Reduction of Inflammatory Cell Infiltration and Local Sympathetic Activity in Angiotensin II-Dependent Hypertension. International Journal of Molecular Sciences, 2021.22(24): p.13678. 31. Grobe, J.L., et al., Prevention of angiotensin II-induced cardiac remodeling by angiotensin-(1–7). American Journal of Physiology-Heart and Circulatory Physiology, 2007. 292(2): p. H736-H742. 32. Molaei, A., et al., Mas receptor: a potential strategy in the management of ischemic cardiovascular diseases. Cell Cycle, 2023.22(13): p.1654-1674. 33. Schirone, L., et al., A Review of the Molecular Mechanisms Underlying the Development and Progression of Cardiac Remodeling. Oxidative Medicine and Cellular Longevity, 2017. 2017: p.1-16. 34. Qi, Y., et al., Lentivirus-mediated overexpression of angiotensin-(1-7) attenuated ischaemia-induced cardiac pathophysiology. Experimental Physiology, 2011.96(9): p.863- 874. 35. Zhu, L., et al., Detection of myocardial fibrosis: Where we stand. Front Cardiovasc Med, 2022.9: p.926378. 36. Berli, A.-S.J., et al., The use of strain, strain rate, and displacement by 2D speckle tracking for assessment of systolic left ventricular function in goats: applicability and influence of general anesthesia. Cardiovascular Ultrasound, 2015.13(1). 37. Evonuk, K.S., et al., Myocardial ischemia / reperfusion impairs neurogenesis and hippocampal-dependent learning and memory. Brain, Behavior, and Immunity, 2017.61: p. 266-273. 38. Hay, M., et al., Angiotensin (1-7) and Mas receptor activation inhibits aldosterone induced ROS inflammatory responses in neurons of the paraventricular nucleus (PVN).2013. 27(696.5).39. 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Claims

UAZ-42224.601 UA23-296 What is claimed is:

1. A method of reducing or treating cardiac ischemic reperfusion injury, comprising administering a therapeutic composition to a subject during and / or after a cardiac ischemic event, wherein the therapeutic composition comprises one or more Ang-(1-7) derivatives.

2. A method of decreasing infarct size in a subject following ischemic reperfusion injury, comprising administering a therapeutic composition to a subject during and / or after a cardiac ischemic event, wherein the therapeutic composition comprises one or more Ang-(1- 7) derivatives.

3. A method of decreasing ischemic reperfusion injury related ventricle fibrosis in a subject following ischemic reperfusion injury, comprising administering a therapeutic composition to a subject during and / or after a cardiac ischemic event, wherein the therapeutic composition comprises one or more Ang-(1-7) derivatives.

4. A method of decreasing ischemic reperfusion injury related heart tissue inflammation in a subject following ischemic reperfusion injury, comprising administering a therapeutic composition to a subject during and / or after a cardiac ischemic event, wherein the therapeutic composition comprises one or more Ang-(1-7) derivatives.

5. A method of decreasing ischemic reperfusion injury related cardiac function deterioration in a subject following ischemic reperfusion injury, comprising administering a therapeutic composition to a subject during and / or after a cardiac ischemic event, wherein the therapeutic composition comprises one or more Ang-(1-7) derivatives.

6. A method of decreasing ischemic reperfusion injury related memory impairment in a subject following ischemic reperfusion injury, comprising administering a therapeutic composition to a subject during and / or after a cardiac ischemic event, wherein the therapeutic composition comprises one or more Ang-(1-7) derivatives.

7. A method of increasing heart function, reducing mortality, reducing cardiac volumes and / or reducing scar size following ischemic reperfusion injury, comprising administering aUAZ-42224.601 UA23-296 therapeutic composition to a subject during and / or after a cardiac ischemic event, wherein the therapeutic composition comprises one or more Ang-(1-7) derivatives.

8. A method of treating myocardial infarction, comprising administering a therapeutic composition to a subject during and / or after a cardiac ischemic event, wherein the therapeutic composition comprises one or more Ang-(1-7) derivatives.

9. A method of inducing cardiomyocyte regeneration, cardiac repair, vasculogenesis and / or cardiomyocyte differentiation following a cardiac ischemic event, comprising administering a therapeutic composition to a subject during and / or after a cardiac ischemic event, wherein the therapeutic composition comprises one or more Ang-(1-7) derivatives.

10. The method of claims 1-9, wheiren each of the Ang-(1-7) derivatives is independently of the formula: A1–A2–A3–A4–A5–A6–A7–A8(SEQ ID NO:1), where A1is selected from the group consisting of aspartic acid, glutamic acid, alanine, and glycosylated forms thereof; A2is selected from the group consisting of arginine, histidine, lysine, and glycosylated forms thereof; A3is selected from the group consisting of valine, alanine, isoleucine, leucine, and glycosylated forms thereof; A4is selected from the group consisting of tyrosine, phenylalanine, tryptophan, and glycosylated forms thereof; A5is selected from the group consisting of isoleucine, valine, alanine, leucine, and glycosylated forms thereof; A6is selected from the group consisting of histidine, arginine, lysine, and glycosylated forms thereof; A7is selected from the group consisting of proline, glycine, serine, and glycosylated forms thereof; and A8can be present or absent, wherein when A8is present, A8is selected from the group consisting of serine, threonine, hydroxyproline, and glycosylated forms thereof, provided (i) at least one of A1-A8is optionally substituted with a mono- or di- carbohydrate; or (ii) when A8is absent: (a) at least one of A1-A7is substituted with a mono- or di-carbohydrate, (b) A7is terminated with an amino group, or (c) a combination thereof.

11. The method of claims 1-9, wheiren each of the Ang-(1-7) derivatives is independently selected from: PNA2, PNA3, PNA4, and PNA5.

12. The method of claims 1-9, wheiren each of the one or more Ang-(1-7) derivatives are PNA5.UAZ-42224.601 UA23-296 13. The method of claims 1-9, wherein the therapeutic composition is a pharmaceutical composition.

14. The method of claims 1-9, wherein administering the therapeutic composition occurs during the cardiac ischemic event.

15. The method of claims 1-9, wherein administering the therapeutic composition occurs concurrent with reperfusion of ischemic cardiac tissue.

16. The method of claims 1-9, wherein administering the therapeutic composition occurs after reperfusion of ischemic cardiac tissue.

17. The method of claims 1-9, wherein the dose is administered in a single administration.

18. The method of claims 1-9, wherein the dose is administered over multiple administrations.

19. The method of claims 1-9, further comprising administrating an effective amount of at least one additional therapeutic agent or at least one additional therapy to the subject for a combination therapy.

20. The method of claim 19, wherein each of the therapeutic composition and the at least one additional therapeutic agent or therapy is administered in a separate formulation or are administered together in a single formulation.

21. The method of claim 19, wherein the therapeutic composition and the at least one additional therapeutic agent or therapy are administered sequentially, are administered concomitantly, and / or are administered in rotation.

22. The method of claim 19, wherein the at least one additional therapeutic agent or therapeutic therapy is selected from the group consisting of Idebenone, Eplerenone, VECTTOR, AVI-4658, Ataluren / PTC124 / Translarna, BMN044 / PRO044, CAT-1004,UAZ-42224.601 UA23-296 microDystrophin AAV gene therapy (SGT-001), Galectin-1 therapy (SB-002), LTBB4 (SB- 001), rAAV2.5-CMV-minidystrophin, glutamine, NFKB inhibitors, sarcoglycan, delta (35 kDa dystrophin-associated glycoprotein), insulin like growth factor-1 (IGF-1) expression, genome editing through the CRISPR / Cas9 system, any gene delivery therapy aimed at reintroducing a functional recombinant version of the dystrophin gene, Exon skipping therapeutics, read-through strategies for nonsense mutations, cell-based therapies, utrophin upregulation, myostatin inhibition, anti-inflammatories / anti-oxidants, mechanical support devices, a biologic drug, a gene therapy or therapeutic gene modulation agent, and combinations thereof.

23. The method of claim 19, wherein the at least one additional therapeutic agent or therapeutic therapy is selected from the group comprising a percutaneous coronary intervention, coronary artery bypass grafting, thrombolytic therapy, anti-platelet therapy, heparin, warfarin, fibrinolytics, oxygen therapy, a vasodilator, pain medication, a beta blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB), a glycoprotein antagonist, a statin, an aldosterone antagonist, an implantable cardiac defibrillator (ICD), or any combination thereof.

24. The method of claims 1-9, wherein reperfusion of ischemic cardiac tissue comprises a percutaneous coronary intervention, coronary artery bypass grafting, thrombolytic therapy, anti-platelet therapy, heparin, warfarin, fibrinolytics, oxygen therapy, a vasodilator, pain medication, a beta blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB), a glycoprotein antagonist, a statin, an aldosterone antagonist, an implantable cardiac defibrillator (ICD), or any combination thereof.

25. The method of claims 1-9, wherein the subject is a mammal, optionally a human.

26. The method of claims 1-9, the subject has or is suspected of having a cardiac disease, wherein the cardiac disease is myocardial infarction, ischemic heart disease, dilated cardiomyopathy, heart failure (e.g., congestive heart failure), ischemic cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, alcoholic cardiomyopathy, viral cardiomyopathy, tachycardia-mediated cardiomyopathy, stress-induced cardiomyopathy, amyloid cardiomyopathy, arrhythmogenic right ventricular dysplasia, left ventricularUAZ-42224.601 UA23-296 noncompaction, endocardial fibroelastosis, aortic stenosis, aortic regurgitation, mitral stenosis, mitral regurgitation, mitral prolapse, pulmonary stenosis, pulmonary regurgitation, tricuspid stenosis, tricuspid regurgitation, congenital disorder, genetic disorder, or any combination thereof.

27. The method of claims 1-9, wherein the subject is affected by a condition selected from the group comprising alcoholic cardiomyopathy, coronary artery disease, congenital heart disease, nutritional diseases affecting the heart, ischemic cardiomyopathy, hypertensive cardiomyopathy, valvular cardiomyopathy, inflammatory cardiomyopathy, cardiomyopathy secondary to a systemic metabolic disease, dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), restrictive cardiomyopathy (RCM), noncompaction cardiomyopathy, supravalvular aortic stenosis (SVAS), vascular scarring, atherosclerosis, chronic progressive glomerular disease, glomerulosclerosis, progressive renal failure, vascular occlusion, hypertension, stenosis, diabetic retinopathy, or any combination thereof.

28. The method of claims 1-9, wherein the cardiac ischemic reperfusion injury comprises cardiac ischemic damage, cardiac reperfusion injury, or a combination thereof.

29. The method of claims 1-9, wherein the administration reduces cardiac ischemic damage, cardiac reperfusion injury, or a combination thereof, as compared to a control subject.

30. The method of claims 1-9, wherein the cardiac ischemic reperfusion injury comprises injuries caused by the cardiac ischemia event, reperfusion injuries, or a combination thereof.

31. The method of claims 1-9, wherein the cardiac ischemic event comprises one or more of myocardial infarction, coronary artery bypass grafting (CABG), cardiac bypass surgery, cardiac transplantation, and angioplasty.

32. The method of claims 1-9, wherein the cardiac ischemic event comprises a vascular interventional procedure employing a stent, laser catheter, atherectomy catheter, angioscopy device, beta or gamma radiation catheter, rotational atherectomy device, coated stent,UAZ-42224.601 UA23-296 radioactive balloon, heatable wire, heatable balloon, biodegradable stent strut, a biodegradable sleeve, or any combination thereof.

33. The method of claims 1-9, wherein the administration induces endogenous cardiomyocyte regeneration.

34. The method of claims 1-9, wherein the administration enhances cardiac function in the subject as compared to a control subject, wherein enhancing cardiac function comprises one or more of (i) improving left ventricular function, (ii) improving fractional shortening, (iii) improving ejection fraction, (iv) reducing end-diastolic volume, (v) decreasing left ventricular mass, and (v) normalizing of heart geometry, or (vi) a combination thereof.

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