Copyright © 2007, European Society of Cardiology
Angiotensin II-mediated oxidative stress and inflammation mediate the age-dependent cardiomyopathy in ACE2 null mice
aDivision of Cardiology, Department of Medicine, University of Toronto, Canada
bDepartment of Medical Biophysics, Ontario Cancer Institute, Toronto, Canada
cDepartment of Physiology, University of Toronto, Canada
dWake Forest University School of Medicine, Winston-Salem, North Carolina, United States
eDivision of Cardiovascular Pathology, Department of Pathology, University Health Network, Canada
fDepartment of Medicine, University of Toronto, Canada
gDivision of Nephrology, Department of Medicine, University of Toronto, Canada
hIMBA, Institute for Molecular Biotechnology of the Austrian Academy of Sciences, Austria
* Corresponding authors. Oudit is to be contacted at Rm 7326, Medical Sciences Building One King's College Circle, University of Toronto, Toronto, Canada M5S 1A8. Tel.: +1 416 665 4788; fax: +1 416 946 2984. Penninger, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohrgasse 3-5, 1030 Vienna, Austria. gavin.oudit{at}utoronto.ca josef.penninger{at}oeaw.ac.at
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
) and its downstream pathways. We showed that p110, the catalytic subunit of PI3K, is a key mediator of NADPH oxidase activation in response to Ang II. The double mutant mice (Ace2–/y/p110–/–) exhibited marked reductions in oxidative stress, neutrophilic infiltration, and pathological hypertrophy resulting in myocardial protection, suggesting that PI3K 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.
KEYWORDS Angiotensin converting enzyme 2; Renin–angiotensin system; Angiotensin II; Oxidative stress; Neutrophils; P13 kinase gamma
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