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.

Angiotensin-converting enzyme-2 overexpression improves atrial electrical remodeling through TRPM7 signaling pathway

“…Thus the Ca 2+ -permeable TRP channels may serve as potential novel targets for developing anti-fibrotic drugs [ 28 ]. Previous studies demonstrated that the overexpression of ACE2 inhibited myocardial fibrosis [ 29 ]. The results of this study suggest that ACE2 reduces TRPM7 expression, leading to an increase in the atrial tissue ERP, suggesting that ACE2 overexpression mediated by TRPM7 mitigates atrial electrical remodeling.…”

Effect of c‐Ski on atrial remodelling in a rapid atrial pacing canine model

“…The inducibility and duration of AF were measured at basic pacing cycle lengths of 300 ms AF induction was defined as P‐wave disappearance and rapid atrial activation with an irregular ventricular response on an atrial electrocardiogram after atrial programmed stimulation (S1 to S2), which was attempted three times at each site. The duration of induced AF was also recorded …”

“…The duration of induced AF was also recorded. 8 Immunohistochemical assays for collagen III and α-SMA were also performed using appropriate antibodies.…”

“…Transforming growth factor β1 (TGF‐β1) is a powerful cytokine affecting a multitude of cellular functions, including differentiation, proliferation and apoptosis. It is a profibrotic cytokine that has been demonstrated to induce selective atrial fibrosis, suggesting its critical role in the pathogenesis of AF . TGF‐β1 exerts its profibrotic effects primarily through phospho‐(p‐) smad2 and phospho‐smad4, and c‐Ski inhibits TGF‐β1 signalling through its interaction with these Smad proteins .…”

“…It is a profibrotic cytokine that has been demonstrated to induce selective atrial fibrosis, suggesting its critical role in the pathogenesis of AF. 7,8 TGF-β1 exerts its profibrotic effects primarily through phospho-(p-) smad2 and phospho-smad4, and c-Ski inhibits TGF-β1 signalling through its interaction with these Smad proteins. 9 c-Ski, a homolog of the v-Ski oncoprotein, is highly conserved across various species and is widely expressed in different tissues, including cardiac tissue.…”