Angiotensin-converting enzyme-2 overexpression improves atrial remodeling and function in a canine model of atrial fibrillation.

Abstract

BackgroundAtrial fibrosis is an important factor in initiating and maintaining atrial fibrillation. The purpose of this study was to test the hypothesis that atrial angiotensin‐converting enzyme‐2 (ACE2) overexpression might inhibit atrial collagen accumulation and improve atrial remodeling in a canine atrial pacing model.Methods and ResultsThirty‐two mongrel dogs of both genders were divided randomly into 4 groups: sham‐operated, control, gene therapy with adenovirus‐enhanced green fluorescent protein (Ad‐EGFP), and gene therapy with Ad‐ACE2. All of the dogs in the control, Ad‐EGFP, and Ad‐ACE2 groups were paced at 450 bpm for a period of 14 days. The dogs in the sham group were instrumented without pacing. After 2 weeks, all of the dogs underwent a thoracotomy operation and received epicardial gene painting. On post–gene transfer day 21, the animals underwent electrophysiology, histology, and molecular studies. The percentage of 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 transforming growth factor‐β1 and 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 reverse transcription polymerase chain reaction.ConclusionsOur results demonstrate that the overexpression of ACE2 inhibits atrial collagen accumulation and improves left atrial remodeling and function in a canine model of atrial fibrillation. Thus, targeted gene ACE2 therapy provides a promising approach for the treatment of atrial fibrillation.