Cardioprotective effects of ghrh agonists

Abstract

Disclosed herein are methods demonstrating that growth-hormone releasing hormone (GHRH) directly activates cellular reparative mechanisms within the injured heart, in a GH / IGF-I independent fashion. Following experimental myocardial infarction (MI), rats were randomly assigned to receive, during a 4 week period, either placebo (n=14), rat recombinant GH (rrGH, n=8) or JI-38 (n=8; 50 μg / Kg / day), a potent GHRH-agonist. JI-38 did not elevate serum levels of GH or IGF-I, but markedly attenuated the degree of cardiac functional decline and remodeling after injury. In contrast, GH administration markedly elevated body weight, heart weight, circulating GH and IGF-I, but did not offset the decline in cardiac structure and function. Whereas, both JI-38 and GH augmented levels of cardiac precursor cell proliferation, only JI-38 increased anti-apoptotic gene expression. Collectively, these findings demonstrate that within the heart, GHRH-agonists can activate cardiac repair following MI.

Description

RELATED APPLICATIONS[0001]This application is a divisional application of U.S. application Ser. No. 12 / 914,023 filed on Oct. 28, 2010, which claims priority to U.S. Provisional Application No. 61 / 289,949 filed Dec. 23, 2009, the contents of each of the foregoing applications are incorporated by reference herein.GOVERNMENT INTEREST[0002]This work was supported by NIH grant R01-AG025017, RO1-HL084275, RO1-HL65455, RO1-HL094848 and by National Heart, Lung, and Blood Institute Grants U54-HL081028. The studies in the laboratory of AVS were supported in part by The Medical Research Service of the Veterans Affairs Department and South Florida Veterans Affairs Foundation for Research and Education and University of Miami, Miller School of Medicine, Departments of Pathology and Medicine, Division of Hematology / Oncology.FIELD OF THE INVENTION[0003]Cardioprotective Effects of GHRH AgonistsSequence Listing[0004]The instant application contains a Sequence Listing which was submitted in ASCII for...

AI Technical Summary

Benefits of technology

GHRH-A treatment leads to improved cardiac structure and function, reduced infarct size, and decreased cardiac fibrosis, achieving better outcomes than traditional GH treatments without weight gain or GH / IGF-I axis stimulation, suggesting a direct cardioprotective effect.

Problems solved by technology

Congestive heart failure remains a leading cause of morbidity and mortality in developed countries.

Despite major therapeutic advances, current therapies fail to fully reverse heart failure and / or left ventricular (LV) dysfunction.

Moreover, several clinical studies have tested the impact of GH replacement on the failing human heart, with controversial results (3,4).

Ghrelin and other GH secretagogues may have pharmacological potential (10), but also have pleiotropic actions with a high possibility of unexpected side effects and potentially serious disadvantages.

Similarly, treatments with rat recombinant GH did not show beneficial effect in rats with large MI (19).

Importantly, all treatments with recombinant human GH in rats had a clear limitation due perhaps to the production of anti-GH antibodies after 2 weeks of treatment (23).

Our findings demonstrate that rrGH markedly increases body weight (BW), heart weight (HW) and circulating levels of GH and IGF-I, but does not improve cardiac function or prevent remodeling; on the contrary, rats treated with rrGH exhibited larger chambers and worse ejection fraction (EF).

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