Application of AngII in preparation of medicine for improving myocardial remodeling

Abstract

The invention discloses an application of AngII in preparation of a medicine for improving myocardial remodeling, and 50-100nM AngII can promote myocardial cells to proliferate and hypertrophy; the AngII of 100-1000 nM induces apoptosis or ferroptosis of myocardial cells, but the phenomenon of cell necrosis does not exist. It is proved for the first time that AngII has dose-effect difference, a small dose of AngII can promote proliferation and hypertrophy of myocardial cells, a large dose of AngII can cause apoptosis and ferroptosis of the myocardial cells, but the phenomenon of cell necrosis does not exist; for the first time, it is found that different pathological changes of myocardial cells can be induced when AngII with different concentrations is given to different areas of the myocardium, so that the myocardium is reconstructed according to design requirements, the heart structure is improved, the expectation of improving the heart function is achieved, and a new treatment strategy is provided for improving myocardial reconstruction.

Description

Technical Field

[0001] The present invention relates to the field of biomedical technology, and in particular to the application of AngII in the preparation of a drug for improving myocardial remodeling. Background Art

[0002] Heart failure (HF) is a multifaceted, life-threatening syndrome characterized by high morbidity and mortality, high healthcare costs, and poor functional and quality of life for patients. There are more than 64 million HF patients worldwide. Currently, the treatment of HF is mainly achieved by inhibiting the production of angiotensin II (AngII), antagonizing its binding to the AT1 receptor (AT1R), and improving myocardial remodeling. AngII is a vasoconstrictor eighth amino acid peptide that increases blood pressure in a complex regulatory and counter-regulatory system. In 2009, experimental work in Gram-negative septic sheep introduced the concept that septic acute kidney injury (AKI) may be partly due to efferent arteriolar vasodilation, and reported significant beneficial effects of AngII infusion on renal function. The drug is currently FDA-approved as a second-line vasopressor for the treatment of catecholamine-refractory vasodilatory shock. In the United States (USA), it has been used in thousands of patients. It is now also approved by the European Medicines Agency (EMA) for the same indication. At the end of 2020, it was used to support blood circulation in hypotensive patients infected with the COVID-19 virus, and is now also being used in cardiac surgery patients.

[0003] It is currently believed that AngII can promote cell proliferation and hypertrophy, induce apoptosis, and cause myocardial remodeling through fibrosis. Therefore, the method of inhibiting AngII production and antagonizing AT1-R is adopted to improve myocardial remodeling. However, due to the limitations of pharmacological properties and usage methods, the drug retention time and accumulation in specific areas of the heart are insufficient, and there is a lot of non-specific distribution, making it difficult to achieve targeted drug action. Summary of the invention

[0004] The purpose of the present invention is to provide the use of AngII in preparing a drug for improving myocardial remodeling in view of the deficiencies in the prior art.

[0005] To achieve the above object, the technical solution adopted by the present invention is:

[0006] The first aspect provides the use of AngII in preparing a drug for improving myocardial remodeling.

[0007] Furthermore, 50-100 nM AngII promoted cardiomyocyte proliferation and hypertrophy.

[0008] Furthermore, 100-1000 nM AngII induced apoptosis or ferroptosis of cardiomyocytes, but there was no cell necrosis.

[0009] The second aspect provides a method for improving myocardial remodeling using AngII, using a percutaneously implantable intracardiac perfusion system to implement targeted perfusion in selected areas within the cardiac cavity and coronary venous system, so as to administer different concentrations to different areas of the myocardium:

[0010] Injection of a small dose of AngII promotes cardiomyocyte proliferation and hypertrophy, while injection of a large dose of AngII induces cardiomyocyte apoptosis or ferroptosis, thereby inducing different pathological changes in cardiomyocytes, causing the myocardium to be reconstructed according to design requirements and improving the heart structure.

[0011] The present invention adopts the above technical solution, and has the following technical effects compared with the prior art:

[0012] The present invention demonstrates for the first time that there are dose-effect differences in AngII, where a small dose can promote cardiomyocyte proliferation and hypertrophy, and a large dose can cause cardiomyocyte apoptosis and ferroptosis, but there is no cell necrosis. It is also the first time that it is discovered that administering different concentrations of AngII to different areas of the myocardium can induce different pathological changes in myocardial cells, allowing the myocardium to be reconstructed as designed, improving the heart structure, and thereby achieving the expected improvement in heart function, providing a new therapeutic strategy for improving myocardial remodeling. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 To explore the effects of different concentrations of angiotensin II on ferroptosis of cardiac microvascular endothelial cells, WB detected the protein expression levels of VEGFA, ALOX12, SLC7A11 and p21.

[0014] Figure 2 To explore the effects of AngII and Losartan on ferroptosis of human cardiac microvascular endothelial cells, the protein expression levels of VEGFA, ALOX12, SLC7A11 and p21 were detected by WB.

[0015] Figure 3 In order to explore the effects of different concentrations of P53 inhibitors Pifithrin-α and Losartan on ferroptosis of human cardiac microvascular endothelial cells, WB detected the protein expression levels of VEGFA, ALOX12, SLC7A11 and p21. DETAILED DESCRIPTION

[0016] The present invention is further described below in conjunction with the accompanying drawings and specific embodiments, but is not intended to be limiting of the present invention. It should be noted that the embodiments and features in the embodiments of the present invention may be combined with each other without conflict.

[0017] Contrary to the current concept of improving myocardial remodeling (currently, cardiovascular diseases are treated by inhibiting the production of Ang II, antagonizing its binding to AT1 receptors, and inhibiting its biological activity), the present invention is based on the characteristic that the physiological effects of Ang II have dose-effect differences. A percutaneously implantable intracardiac perfusion system is used to implement targeted perfusion in selected areas within the cardiac cavity and coronary venous system. Different concentrations of AngII are administered to different areas of the myocardium to induce hypertrophy or apoptosis and ferroptosis of myocardial cells, artificially induce myocardial remodeling, and achieve the purpose of improving the heart structure. Ang II itself is a peptide that can be produced inside the body and will not cause necrotic cell death. High concentrations can induce cell apoptosis and ferroptosis, which has few side effects and can relatively gently and safely thin the hypertrophic myocardium, thereby achieving the purpose of relieving obstruction.

[0018] Among them, 50-100nM AngII promotes cell proliferation and hypertrophy; 100-1000nM AngII induces cell apoptosis or ferroptosis, but there is no cell necrosis.

[0019] The structural formula of the above AngII is as follows, molecular weight 1106.23, molecular formula: C 52 H 75 N 13 O 14

[0020]

[0021] Example

[0022] 1.1 Investigating the effects of different concentrations of angiotensin II on ferroptosis of cardiac microvascular endothelial cells

[0023] Experimental groups: 1) AngII 0 μM;

[0024] 2) AngII 1 μM;

[0025] 3) AngII 10 μM;

[0026] 4) AngII 100 μM;

[0027] Human cardiac microvascular endothelial cells (CMVECs) were treated with the above concentrations of AngII for 48 h.

[0028] Detection indicators: Western blot was used to detect the expression levels of VEGFA and ferroptosis-related proteins ALOX12 (PMID: 30962574); SLC7A11 (PMID: 29800655) and p21.

[0029] The results show that ( Figure 1 ), compared with the control group, the expressions of SLC7A11, p21 and VEGFA proteins in CMVECs cells were significantly downregulated after treatment with 1 μM and 100 μM AngII.

[0030] Therefore, after the above experiments and clinical research analysis, ideally, a concentration of 100-1000nM AngII is selected to induce cell apoptosis or ferroptosis.

[0031] 1.2 To explore the effects of AngII and Losartan on ferroptosis of human cardiac microvascular endothelial cells.

[0032] Experimental groups: 1) AngII + 0 μM Losartan (angiotensin II receptor antagonist);

[0033] 2) AngII + 10 μM Losartan;

[0034] AngII (1 μM), which affects ferroptosis of CMVECs, was used in combination with the above-mentioned different concentrations of Losartan to act on CMVECs for 48 hours.

[0035] Detection indicators: Western blot was used to detect the expression levels of VEGFA and ferroptosis-related proteins ALOX12, SLC7A11 and p21.

[0036] The results show that ( Figure 2 ), compared with the control group, after Losartan was used in combination with cells, the expression of ALOX12 protein was not downregulated, and the protein expression levels of SLC7A11 and p21 were not upregulated.

[0037] 1.3 To investigate the effects of different concentrations of P53 inhibitors Pifithrin-α and Losartan on ferroptosis of human cardiac microvascular endothelial cells. AngII and Losartan were used at the optimal concentrations and acted on CMVECs for 48 hours.

[0038] Experimental groups: 1) AngII;

[0039] 2) AngII + 10 μM P53 inhibitor Pifithrin-α;

[0040] 3) AngII+Losartan;

[0041] 4) AngII+Losartan+10μM P53 inhibitor

[0042] Detection indicators: Western blot was used to detect the expression levels of VEGFA and ferroptosis-related proteins ALOX12, SLC7A11 and p21.

[0043] The results show that ( Figure 3 ), compared with the AngII group, the P21 and SLC7A11 proteins in the AngII+10μM Pofithrin-α group were not upregulated, and the expression of VEGFA and ALOX12 proteins was downregulated; the P21 and VEGFA proteins in the AngII+Losartan group were upregulated, the expression of ALOX12 protein was downregulated, and the SLC7A11 protein was not upregulated. Compared with the AngII+Losartan group, the P21 and SLC7A11 proteins in the AngII+Losartan+10μM Pofithrin-α group were not upregulated, the expression of VEGFA protein was slightly downregulated, and the expression of ALOX12 protein was downregulated.

[0044] The above description is only a preferred embodiment of the present invention, and does not limit the implementation mode and protection scope of the present invention. For those skilled in the art, it should be aware that all solutions obtained by equivalent substitutions and obvious changes made using the contents of the specification and illustrations of the present invention should be included in the protection scope of the present invention.

Claims

1. Application of AngII in the preparation of drugs for improving myocardial remodeling.

2. The use according to claim 1, characterized in that: 50-100nM AngII induces cardiomyocyte proliferation and hypertrophy.

3. The use according to claim 1, characterized in that: 100-1000nM AngII induced apoptosis or ferroptosis of cardiomyocytes, but no cell necrosis.

4. A method for improving myocardial remodeling using AngII, characterized in that: Using a percutaneously implantable intracardiac perfusion system, targeted perfusion is performed in selected areas within the cardiac cavity and coronary venous system, giving different concentrations to different areas of the myocardium: Injection of a small dose of AngII promotes cardiomyocyte proliferation and hypertrophy, while injection of a large dose of AngII induces cardiomyocyte apoptosis or ferroptosis, thereby inducing different pathological changes in cardiomyocytes, causing the myocardium to be reconstructed according to design requirements and improving the heart structure.

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