Gene therapy with Angiotensin-(1-9) preserves left ventricular systolic function after myocardial infarction

Fattah, C. et al. (2016) Gene therapy with Angiotensin-(1-9) preserves left ventricular systolic function after myocardial infarction. Journal of the American College of Cardiology, 68(24), pp. 2652-2666. (doi:10.1016/j.jacc.2016.09.946) (PMID:27978950) (PMCID:PMC5158000)

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Abstract

BACKGROUND: Angiotensin-(1-9) [Ang-(1-9)] is a novel peptide of the counter-regulatory axis of the renin angiotensin system previously demonstrated to have therapeutic potential in hypertensive cardiomyopathy when administered via osmotic minipump in mice. Here, we investigate whether gene transfer of Ang-(1-9) is cardioprotective in a murine model of myocardial infarction (MI). OBJECTIVES: To evaluate 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 (LV) 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) significantly 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 increasing contractility. Ang-(1-9) increased contraction in the Langendorff model through a protein kinase A-dependent mechanism. CONCLUSIONS: Our novel findings show that Ang-(1-9) gene therapy preserves LV systolic function post-MI, restoring cardiac function. Furthermore, Ang-(1-9) has a direct effect on cardiomyocyte 3 calcium handling through a protein kinase A-dependent mechanism. These data highlight Ang-(1-9) gene therapy as a potential new strategy in the context of MI.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Zamora Rodriguez, Dr Victor and Nicklin, Professor Stuart and Smith, Professor Godfrey and Flores, Dr Monica and Hortigon, Dr Maria and McCarroll, Dr Charlotte and Loughrey, Dr Christopher and McArthur, Dr Lisa and Touyz, Professor Rhian
Authors: Fattah, C., Nather, K., McCarroll, C. S., Hortigon-Vinagre, M. P., Zamora Rodriguez, V., Flores-Munoz, M., McArthur, L., Zentilin, L., Giacca, M., Touyz, R. M., Smith, G. L., Loughrey, C. M., and Nicklin, S. A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Journal of the American College of Cardiology
Publisher:Elsevier
ISSN:0735-1097
ISSN (Online):1558-3597
Published Online:12 December 2016
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Journal of the American College of Cardiology 68(24):2652-2666
Publisher Policy:Reproduced under a Creative Commons License
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
570291Angiotensin 1-9 and angiotensin 1-7: assessment of their mechanisms of action as counter-regulatory renin angiotensin system peptides in cardiovascular diseaseStuart NicklinBritish Heart Foundation (BHF)PG/11/43/28901RI CARDIOVASCULAR & MEDICAL SCIENCES
660151Priming Innovative Translational Research - The University of Glasgow Confidence in Concept ProgrammeAnna DominiczakMedical Research Council (MRC)MC_PC_13063RI CARDIOVASCULAR & MEDICAL SCIENCES
519461Dissecting the mechanism of action of the novel renin angiotensin hormone angiotensin1-9Stuart NicklinMedical Research Council (MRC)G0901161RI CARDIOVASCULAR & MEDICAL SCIENCES