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 Smith, Professor Godfrey and Flores, Dr Monica and Loughrey, Professor Christopher and McArthur, Dr Lisa and Nicklin, Professor Stuart and Hortigon, Dr Maria and Touyz, Professor Rhian and McCarroll, Dr Charlotte |
| 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 > School of Cardiovascular & Metabolic Health |
| 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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