Abstract 10878: Angiotensin Converting Enzyme 2 (ACE2) Deficiency Activates NADPH Oxidase Resulting in Endothelial Dysfunction and Worsens Diabetic Cardiomyopathy
OBJECTIVES: Incidence of heart disease and severity of heart failure is greater in diabetics compared with non-diabetics. The renin-angiotensin system is activated in diabetics leading to increased angiotensin II (Ang II) formation. Angiotensin converting enzyme 2 (ACE2) degrades Ang II to Ang 1-7, which has the capacity to counter the actions of Ang II.
METHODS: To define the role of ACE2 in diabetic cardiovascular complications, we examined cardiac and vascular function by echocardiography, hemodynamics, flow-mediated dilation and molecular signaling in male mice with genetic ablation of ACE2 in the context of the Akita model of type 1 diabetes.
RESULTS: Type 1 diabetic cardiomyopathy in the Akita mouse model is characterized by moderate diastolic dysfunction with preserved systolic function. Myocardial ACE2 level is increased in the diabetic Akita mice. Loss of ACE2 in Akita mice resulted in systolic dysfunction, (ejection fraction: 49.9±2.5% vs 62.7±2.4% (WT), Akita (60.4±2%) and 63.1±1.7% (ACE2KO); n=10; p<0.05) with a restrictive diastolic filling pattern. ACE2 deficiency enhanced protein kinase C-dependent activation of NADPH oxidase and generation of superoxide as detected by DHE staining and NADPH oxidase activity based on the chemiluminescence lucigenin assay. Furthermore, Akita/ACE2KO myocardium exhibited increased phosphorylation of Jak2, Stat3 and ERK1/2 signaling pathways, in addition to enhanced matrix metalloproteinase (MMP)-2 and MMP-9 activation. Plasma Ang II levels were significantly elevated in ACE2/Akita double mutant (123±17 pg/ml, n=12, p<0.05) versus WT (41.6±6.1), Akita (36.9±6.3) and ACE2KO (50.5±7.4). Endothelial-dependent vasodilation in vivo as assessed by flow-mediated dilation of the femoral artery was markedly impaired in the ACE2/Akita double mutant mice with increased superoxide generation detected by DHE staining.
CONCLUSIONS: Loss of ACE2 increases Ang II level, induces oxidative stress and modulation of pathological signaling which in combination with endothelial dysfunction underlies impaired systolic function in diabetic cardiomyopathy. Enhancing ACE2 action may prevent the diabetic cardiovascular complications.
- © 2011 by American Heart Association, Inc.