ACE2 Overexpression Ameliorates Left Ventricular Remodeling and Dysfunction in a Rat Model of Myocardial Infarction

Abstract

The purpose of this study was to test the hypothesis that overexpression of angiotensin-converting enzyme 2 (ACE2) may favorably affect left ventricular (LV) remodeling and function after myocardial infarction (MI). The left anterior descending coronary artery was ligated to produce anterior MI in 100 Wistar-Kyoto rats that were randomly divided into Ad-ACE2, Ad-ACE2+A779, Ad-EGFP, model, and sham groups. Two weeks later, rats in the Ad-ACE2 and Ad-EGFP groups received direct intramyocardial injection of Ad-ACE2 and Ad-EGFP, respectively. Rats in the Ad-ACE2+A779 group received both intramyocardial injection of Ad-ACE2 and a continuous intravenous infusion of A779 for 15 days. LV volume and systolic function, the extent of myocardial fibrosis, and levels of ACE2, angiotensin II (Ang II), and collagen I protein expression were evaluated. Four weeks after ACE2 gene transfer, the Ad-ACE2 group showed reduced LV volume, extent of myocardial fibrosis, and expression levels of ACE, Ang II, and collagen I in the myocardium, and increased LV ejection fraction and levels of ACE2 activity and expression in comparison with the Ad-EGFP and model groups. These results suggest that ACE2 overexpression attenuated LV fibrosis and improved LV remodeling and systolic function. In conclusion, overexpression of ACE2 favorably affected the pathological process of LV remodeling after MI by inhibiting ACE activity, reducing AngII levels, and up-regulating Ang-(1-7) expression, thus providing a potential therapeutic target in the treatment of heart failure.

Recombinant Human Angiotensin-Converting Enzyme 2 as a New Renin-Angiotensin System Peptidase for Heart Failure Therapy

“…Myocardial levels of Ang II and Ang 1-7 were increased and decreased, respectively, resulting in greater inflammation, NADPH oxidase activation, and degradation of the extracellular matrix [35]. Consistent with a key role of ACE2 in post-MI remodeling, overexpression of ACE2 ameliorates left ventricular remodeling and dysfunction in a rat model of MI [36]. In the human population, genetic variability in the ace2 gene correlates with susceptibility to cardiovascular disease [37][38][39].…”

Role of ACE2 in diastolic and systolic heart failure

“…Single nucleotides polymorphisms (SNPs) of ACE2 are associated with variation in left ventricular mass, septal wall thickness and ventricular hypertrophy [35], coronary heart disease and myocardial infarction [36], and hypertension in patients with metabolic syndrome [37]. Consistent with a key role of ACE2 in post-MI remodeling, overexpression of ACE2 ameliorates left ventricular remodeling and dysfunction in a rat model of myocardial infarction [38]. In addition, cultured fibroblasts infected with ACE2 lentivirus show a decreased production of collagen induced by acute hypoxic exposure [39].…”

The pathogenesis and treatment of cardiac atrophy in cancer cachexia

“…ANG-(1-7) signaling is mediated through the mitochondrial assembly receptor (MasR), and signaling via this pathway has cardioprotective effects including improving LV remodeling and function in rodent models of diabetic cardiomyopathy (32) and myocardial infarction (29,121). However, the clinical benefits of targeting this pathway in cardiac cachexia in cancer have yet to be examined.…”