Journal
CARDIOVASCULAR RESEARCH
Volume 75, Issue 1, Pages 29-39Publisher
OXFORD UNIV PRESS
DOI: 10.1016/j.cardiores.2007.04.007
Keywords
angiotensin converting enzyme 2; renin-angiotensin system; angiotensin II; oxidative stress; neutrophils; P13 kinase gamma
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Objectives: The peptidase action of angiotensin converting enzyme 2 (ACE2) allows it to function as a negative regulator of the renin-angiotensin system. Current pharmacotherapies for human heart failure, such as ACE inhibitors and angiotensin and aldosterone receptor blockers, increase the activity of ACE2 in the heart. In this study, we investigate the mechanism for the age-dependent cardiomyopathy in ACE2 null mice. Methods and results: Ace2(-/y) mutant mice develop a progressive age-dependent dilated cardiomyopathy with increased oxidative stress, neutrophilic infiltration, inflammatory cytokine and collagenase levels, mitogen-activated protein kinase (MAPK) activation and pathological hypertrophy. The angiotensin II receptor-1 (AT1) blocker, irbesartan, prevented the dilated cardiomyopathy in aged Ace2(-/y) mutant mice, confirming a critical role of angiotensin II (Ang II)-mediated stimulation of AT1 receptors: Ang II activation of AT1 receptors triggers G-protein-coupled receptor (GPCR)-activated phosphoinositide 3-kinase gamma (PI3K gamma) and its downstream pathways. We showed that p110 gamma, the catalytic subunit of PI3K gamma, is a key mediator of NADPH oxidase activation in response to Ang II. The double mutant mice (Ace2(-/y)/p110 gamma(-/-)) exhibited marked reductions in oxidative stress, neutrophilic infiltration, and pathological hypertrophy resulting in myocardial protection, suggesting that PI3K gamma plays a critical role in Ang II-mediated cardiomyopathy. Conclusions: Our findings demonstrate that the age-dependent cardiomyopathy in ACE2 null mice is related to increased Ang II-mediated oxidative stress and neutrophilic infiltration via AT1 receptors. Our combination of genetic and pharmacological approaches defines a critical role of ACE2 in the suppression of Ang II-mediated heart failure. (c) 2007 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
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