Overexpression Of ACE2 Improves The Canine Atrial Remodeling And Function

Background:Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia with a relevant effect on mortality and morbidity, especially in the elderly. Moreover, the rapid heart rate resulting from AF could cause a number of adverse outcomes, including congestive heart failure and stroke. The current treatment for AF includes drug therapy and ablative strategies. In patients with persistent AF, however, the relapse rate is higher. The poor curative effect in patients with persistent AF is mainly due to atrial fibrosis. Several studies have revealed that the renin-angiotensin system (RAS) is associated with the development of AF. Angiotensin converting enzyme II (ACE2), an enzyme identified in rodents and humans with a more restricted distribution than ACE, is expressed mainly in the heart and kidney. ACE2 cleaves AngⅡ, the main effector of the RAS, to form the vasodilator Ang-(1-7). The results suggest that ACE2 negatively regulates activated RAS.Thus, ACE2 may have an important role in fibrosis formation duringAF. However, the regulatory mechanism of ACE2 in AF is largely unexplored.Objective:The purpose of this study was to test the hypothesis that atrial angiotensin-converting enzyme-2 overexpression might inhibit atrial collagen accumulation and improve atrial remodeling in a canine model of atrial fibrillation.Methods:Thirty-two mongrel dogs of both genders were divided randomly into four groups:Sham-operated, control, gene therapy with Ad-EGFP and gene therapy with Ad-ACE2. All of the dogs in the Ad-EGFP, Control and Ad-ACE2 groups were paced at 450 beats per minute for a period of 2 weeks. All dogs of the Sham group without pacing. After 2 weeks, four group dogs underwent a thoracotomy operation, and than, received epicardial gene painting. After gene transfer 3 weeks, the animals underwent electrophysiology, histology and molecular studies.Results:After gene transfer three weeks, atrial fibrillation became inducible in all Ad-EGFP and Control dogs, the duration and inducibility of atrial fibrillation increased obviously compared with the Sham groups. The percentage of atrial tissue fibrosis in the Ad-ACE2 group was markedly lower than the percentage in the Control and Ad-EGFP groups. Compared with the other groups, ACE2 expression was increased significantly in the Ad-ACE2 group. Compared with the Sham and Ad-ACE2 groups, the expression levels of Collagen Ⅰ, Collagen Ⅲ, TGF-β1and Smad3 were significantly higher in the Ad-EGFP and control groups; however, the expression levels of Smad7 were lower in the atrial tissue as detected by Western blot and real time RT-PCR.Conclusions:Our study results demonstrate that the overexpression of ACE2 inhibits atrial collagen accumulation and improves atrial remodeling and function in a canine model of AF.