Loss of angiotensin-converting enzyme 2 accelerates maladaptive left ventricular remodeling in response to myocardial infarction.
BACKGROUND
Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase that metabolizes Ang II into Ang 1-7, thereby functioning as a negative regulator of the renin-angiotensin system. We hypothesized that ACE2 deficiency may compromise the cardiac response to myocardial infarction (MI).


RESULTS
In response to MI (induced by left anterior descending artery ligation), there was a persistent increase in ACE2 protein in the infarct zone in wild-type mice, whereas loss of ACE2 enhanced the susceptibility to MI, with increased mortality, infarct expansion, and adverse ventricular remodeling characterized by ventricular dilation and systolic dysfunction. In ACE2-deficient hearts, elevated myocardial levels of Ang II and decreased levels of Ang 1-7 in the infarct-related zone was associated with increased production of reactive oxygen species. ACE2 deficiency leads to increased matrix metalloproteinase (MMP) 2 and MMP9 levels with MMP2 activation in the infarct and peri-infarct regions, as well as increased gelatinase activity leading to a disrupted extracellular matrix structure after MI. Loss of ACE2 also leads to increased neutrophilic infiltration in the infarct and peri-infarct regions, resulting in upregulation of inflammatory cytokines, interferon-gamma, interleukin-6, and the chemokine, monocyte chemoattractant protein-1, as well as increased phosphorylation of ERK1/2 and JNK1/2 signaling pathways. Treatment of Ace2(-)(/y)-MI mice with irbesartan, an AT1 receptor blocker, reduced nicotinamide-adenine dinucleotide phosphate oxidase activity, infarct size, MMP activation, and myocardial inflammation, ultimately resulting in improved post-MI ventricular function.


CONCLUSIONS
We conclude that loss of ACE2 facilitates adverse post-MI ventricular remodeling by potentiation of Ang II effects by means of the AT1 receptors, and supplementing ACE2 can be a potential therapy for ischemic heart disease.
Kassiri
Zamaneh
Z
Department of Physiology, University of Alberta, Edmonton, Canada.
Zhong
Jiuchang
J
Guo
Danny
D
Basu
Ratnadeep
R
Wang
Xiuhua
X
Liu
Peter P
PP
Scholey
James W
JW
Penninger
Josef M
JM
Oudit
Gavin Y
GY
D000222:Adaptation, Physiological; D000803:Angiotensin I; D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D004195:Disease Models, Animal; D004789:Enzyme Activation; D018836:Inflammation Mediators / Q000378:metabolism; D000077405:Irbesartan; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000172:deficiency* / Q000235:genetics; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D013997:Time Factors; D014463:Ultrasonography; D020257:Ventricular Remodeling / Q000187:drug effects
D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D018836:Inflammation Mediators; D010446:Peptide Fragments; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D013481:Superoxides; D000804:Angiotensin II; D000803:Angiotensin I; D020928:Mitogen-Activated Protein Kinases; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; D020782:Matrix Metalloproteinases; C118790:angiotensin I (1-7); D000077405:Irbesartan