Onset of experimental severe cardiac fibrosis is mediated by overexpression of angiotensin-converting enzyme 2

Masson, R. et al. (2009) Onset of experimental severe cardiac fibrosis is mediated by overexpression of angiotensin-converting enzyme 2. Hypertension, 53(4), pp. 694-700. (doi:10.1161/HYPERTENSIONAHA.108.122333)

Masson, R. et al. (2009) Onset of experimental severe cardiac fibrosis is mediated by overexpression of angiotensin-converting enzyme 2. Hypertension, 53(4), pp. 694-700. (doi:10.1161/HYPERTENSIONAHA.108.122333)

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Abstract

Angiotensin-converting enzyme (ACE) 2 is a recently identified homologue of ACE. There is great interest in the therapeutic benefit for ACE2 overexpression in the heart. However, the role of ACE2 in the regulation of cardiac structure and function, as well as maintenance of systemic blood pressure, remains poorly understood. In cell culture, ACE2 overexpression led to markedly increased myocyte volume, assessed in primary rabbit myocytes. To assess ACE2 function in vivo, we used a recombinant adeno-associated virus 6 delivery system to provide 11-week overexpression of ACE2 in the myocardium of stroke-prone spontaneously hypertensive rats. ACE2, as well as the ACE inhibitor enalapril, significantly reduced systolic blood pressure. However, in the heart, ACE2 overexpression resulted in cardiac fibrosis, as assessed by histological analysis with concomitant deficits in ejection fraction and fractional shortening measured by echocardiography. Furthermore, global gene expression profiling demonstrated the activation of profibrotic pathways in the heart mediated by ACE2 gene delivery. This study demonstrates that sustained overexpression of ACE2 in the heart in vivo leads to the onset of severe fibrosis.

Item Type:Articles
Keywords:ACE2, gene delivery, adeno-associated virus, hypertension, myocardium
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Smith, Professor Godfrey and Nicklin, Professor Stuart and Shirley, Dr Rachel and Baker, Professor Andrew and Graham, Dr Delyth and McBride, Dr Martin and Dominiczak, Professor Anna and Craig, Dr Margaret
Authors: Masson, R., Nicklin, S. A., Craig, M. A., McBride, M., Gilday, K., Gregorevic, P., Allen, J. M., Chamberlain, J. S., Smith, G., Graham, D., Dominiczak, A. F., Napoli, C., and Baker, A. H.
Subjects:Q Science > QH Natural history > QH345 Biochemistry
R Medicine > RC Internal medicine
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Hypertension
Publisher:American Heart Association
ISSN:0194-911X
ISSN (Online):1524-4563
Published Online:16 February 2009
Copyright Holders:Copyright © 2009 American Heart Association
First Published:First published in Hypertension 53(4):694-700
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
449191Does ACE2 have a protective role in the heart? Systematic analysis of ACE2 in a disease modelAndrew BakerBritish Heart Foundation (BHF)PG/07/015/22372Institute of Cardiovascular and Medical Sciences