Journal
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
Volume 68, Issue 24, Pages 2652-2666Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jacc.2016.09.946
Keywords
adeno-associated virus; calcium; inotropy; renin angiotensin system
Categories
Funding
- British Heart Foundation [FS/09/052/28032]
- BHF [PG/11/43/28901]
- MRC Confidence in Concept Award [MC_PC_13063]
- MRC Research Grant [G0901161]
- Fundacion Alfonso Martin Escudero, Spain
- British Heart Foundation [PG/11/43/28901, RG/13/7/30099] Funding Source: researchfish
- Medical Research Council [G0901161, MC_PC_13063] Funding Source: researchfish
- MRC [G0901161, MC_PC_13063] Funding Source: UKRI
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BACKGROUND Angiotensin-(1-9) [Ang-(1-9)] is a novel peptide of the counter-regulatory axis of the renin-angiotensin-aldosterone system previously demonstrated to have therapeutic potential in hypertensive cardiomyopathy when administered via osmotic mini-pump. Here, we investigate whether gene transfer of Ang-(1-9) is cardioprotective in a murine model of myocardial infarction (MI). OBJECTIVES The authors evaluated effects of Ang-(1-9) gene therapy on myocardial structural and functional remodeling post-infarction. METHODS C57BL/6 mice underwent permanent left anterior descending coronary artery ligation and cardiac function was assessed using echocardiography for 8 weeks followed by a terminal measurement of left ventricular pressure volume loops. Ang-(1-9) was delivered by adeno-associated viral vector via single tail vein injection immediately following induction of MI. Direct effects of Ang-(1-9) on cardiomyocyte excitation/contraction coupling and cardiac contraction were evaluated in isolated mouse and human cardiomyocytes and in an ex vivo Langendorff-perfused whole-heart model. RESULTS Gene delivery of Ang-(1-9) reduced sudden cardiac death post-MI. Pressure volume measurements revealed complete restoration of end-systolic pressure, ejection fraction, end-systolic volume, and the end-diastolic pressure volume relationship by Ang-(1-9) treatment. Stroke volume and cardiac output were significantly increased versus sham. Histological analysis revealed only mild effects on cardiac hypertrophy and fibrosis, but a significant increase in scar thickness. Direct assessment of Ang-(1-9) on isolated cardiomyocytes demonstrated a positive inotropic effect via increasing calcium transient amplitude and contractility. Ang-(1-9) increased contraction in the Langendorff model through a protein kinase A-dependent mechanism. CONCLUSIONS Our novel findings showed that Ang-(1-9) gene therapy preserved left ventricular systolic function post-MI, restoring cardiac function. Furthermore, Ang-(1-9) directly affected cardiomyocyte calcium handling through a protein kinase A-dependent mechanism. These data emphasized Ang-(1-9) gene therapy as a potential new strategy in the context of MI. (C) 2016 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.
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