GW24-e3174 A trial overexpression of ACE2 improves the canine rapid atrial pacing-induced structural remodelling

Objectives Atrial fibrillation (AF) is associated with significant morbidity and mortality. Substantial evidence suggests that the renin angiotensin system (RAS) has a role in the pathogenesis of AF. Angiotensin-converting enzyme 2 (ACE2), a monocarboxypeptidase capable of metabolising angiotensin II (Ang II) into angiotensin-(1-7) [Ang-(1-7)], has emerged as a potential therapeutic target. The purpose of this study was to investigate whether atrial overexpression of ACE2 by homogeneous transmural atrial gene transfer can reverse AF induced atrial remodelling and their mechanisms in a canine atrial pacing model. Methods Twenty-eight mongrel dogs were randomly divided into 4 groups: Sham-operated, control, gene therapy with Ad-EGFP (adenovirus-enhanced green fluorescent protein) and gene therapy with Ad-ACE2 (Ad-ACE2 group) (n = 7 per subgroup). Sustained AF was induced in all dogs besides Sham-operated group by atrial rapid pacing at 450 beats/min for 2 weeks. All dogs underwent an invasive electrophysiology study, then receveid epicardial gene painting. Three weeks after gene transfer, all animals underwent repeat electrophysiology study, histology, and molecular studies. Results The Ad-ACE2 group showed increased ACE2, Angiotensin-(1-7) and AT2R expression, and decreased Angiotensin II and AT1R expression in comparison with Ad-EGFP and control groups. ACE2 overexpression attenuated atrial tachypacing induced increase in the levels of activated extracellular signal-regulated kinases (ERK1/2) and mitogen-activated protein kinases (p38MAPK), and decrease in the levels of MAPK phosphatase 1, resulting in attenuation of atrial fibrosis marker, collagen protein and transforming growth factor-β1. Additionally, ACE2 overexpression also ameliorated tachypacing-induced up regulation of connexin 40 and down regulation of connexin 43, Cav1.2 and Kv4.2, and significantly decreased the inducibility and duration of AF. Conclusions ACE2 overexpression could shift the RAS balance towards the protective axis, attenuate cardiac fibrosis remodelling associated with up-regulation of MKP-1 to reduce MAPK activities, ameliorate tachypacing-induced ion channel and connexin remodelling, and subsequently reduce the inducibility and duration of AF. Therefore, overexpression of ACE2 by homogeneous transmural atrial gene transfer could improve atria electrical and structural remodelling in a canine atrial pacing model.