Angiotensin II-mediated oxidative stress and inflammation mediate the age-dependent cardiomyopathy in ACE2 null mice.
OBJECTIVE
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.


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 (PI3Kgamma) and its downstream pathways. We showed that p110gamma, the catalytic subunit of PI3Kgamma, is a key mediator of NADPH oxidase activation in response to Ang II. The double mutant mice (Ace2(-/y)/p110gamma(-/-)) exhibited marked reductions in oxidative stress, neutrophilic infiltration, and pathological hypertrophy resulting in myocardial protection, suggesting that PI3Kgamma 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.
Oudit
Gavin Y
GY
Division of Cardiology, Department of Medicine, University of Toronto, Canada. gavin.oudit@utoronto.ca
Kassiri
Zamaneh
Z
Patel
Mikin P
MP
Chappell
Mark
M
Butany
Jagdish
J
Backx
Peter H
PH
Tsushima
Robert G
RG
Scholey
James W
JW
Khokha
Rama
R
Penninger
Josef M
JM
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors; D000375:Aging / Q000502:physiology; D000804:Angiotensin II / Q000378:metabolism*; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D015153:Blotting, Western; D002311:Cardiomyopathy, Dilated / Q000378:metabolism*; D058544:Class Ib Phosphatidylinositol 3-Kinase; D000077405:Irbesartan; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008163:Luminescent Measurements; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism*; D018384:Oxidative Stress; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013481:Superoxides / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; D000804:Angiotensin II; D000085962:Angiotensin-Converting Enzyme 2; D001713:Biphenyl Compounds; D058544:Class Ib Phosphatidylinositol 3-Kinase; D000077405:Irbesartan; D007527:Isoenzymes; D007703:Peptidyl-Dipeptidase A; D019869:Phosphatidylinositol 3-Kinases; D013481:Superoxides; D013777:Tetrazoles; C119712:Agtrap protein, mouse; C546760:PIK3CG protein, human; C546764:Pik3cg protein, mouse; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse