Published Online
on June 15, 2009

A more recent version of this article appeared on September 1, 2009

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Original Article

Loss of ACE2 accelerates maladaptive left ventricular remodeling in response to myocardial infarction

Zamaneh Kassiri¹; Jiuchang Zhong¹; Danny Guo¹; Rathnadeep Basu¹; Xiuhua Wang¹; Peter P. Liu²; James W. Scholey²; Josef M. Penninger³ and Gavin Y. Oudit^1,4

¹ University of Alberta; Mazankowski Alberta Heart Institute, Edmonton, Canada;
² University of Toronto, Toronto, Canada;
³ IMBA of the Austrian Academy of Sciences, Vienna, Austria

⁴ E-mail: gavin.oudit{at}ualberta.ca

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).

Methods and Results—In response to myocardial infarction (induced by LAD ligation), there was a persistent increase in ACE2 protein in the infarct zone in wild type mice, while loss of ACE2 enhanced the susceptibility to myocardial infarction with increased mortality, infarct expansion and adverse ventricular remodeling characterized by ventricular dilation and systolic dysfunction. In ACE2-deficient hearts, elevated and decreased myocardial levels of levels of Ang II and decreased Ang 1-7, respectively, in the infarct-related zone was associated with increased production of reactive oxygen species. ACE2-deficiency leads to increased MMP2 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 following MI. Loss of ACE2 also lead 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 NADPH oxidase activity, infarct size, MMP activation and myocardial inflammation ultimately resulting in improved post-MI ventricular function.

Conclusion—We conclude that loss of ACE2 facilitates adverse post-MI ventricular remodeling by potentiation of Ang II effects via the AT1 receptors, and supplementing ACE2 can be a potential therapy for ischemic heart disease.

Key Words: angiotensin • heart failure • molecular biology • myocardial infarction • angiotensin II