Inhibition of NADPH oxidase up-regulates connexin 43 and ameliorates electrical remodeling in rabbits with heart failure

Abstract

Background We hypothesized that inhibition of NADPH oxidase by apocynin can ameliorate electrical remodeling and exert antiarrhythmogenic effect by up-regulating connexin 43 (Cx43) in rabbits with heart failure (HF). Methods HF was induced by volume overload plus pressure overload. Rabbits with HF or sham operation were randomized to orally receive apocynin, an inhibitor of NADPH oxidase (15 mg per day) or placebo for eight weeks. Eight weeks after surgery, QRS duration, monophasic action potential duration (MAPD), effective refractory period (ERP), the inducibility of ventricular arrhythmia and ventricular fibrillation threshold (VFT) were evaluated by in vivo electrophysiological study. The Cx43 expression was examined by Real-time PCR and Western blot. Results Apocynin treatment reduced QRS duration, shortened MAPD at 90% repolarization (MAPD 90) and ERP in rabbits with HF. The vulnerability for ventricular arrhythmias was increased in HF hearts, and this increased vulnerability to arrhythmias was reversed by apocynin. The HF rabbits exhibited a marked decrease in VFT compared with sham rabbits, but this decrease was ameliorated by apocynin. Compared with sham-operated rabbits, the total Cx43 mRNA and protein expression and the phosphorylated Cx43 protein were decreased in the HF rabbits, but the reduction was reversed by apocynin. Conclusion Inhibition of NADPH oxidase increases Cx43 expression, ameliorates electrical remodeling and exerts antiarrhythmogenic effect in rabbits with HF. Inhibition of NADPH oxidase could have the potential to become a new antiarrhythmic preventive therapy for HF.