<scp>TRPV2</scp> Inhibition Prevents Right Ventricular Remodeling and Arrhythmia in Experimental Pulmonary Hypertension

Right ventricular (RV) failure and malignant arrhythmia are determinants of the prognosis of pulmonary arterial hypertension (PAH). Transient receptor potential vanilloid type 2 (TRPV2) is involved in the development of heart failure, whereas its role in PAH deserves further exploration. This study aimed to explore whether TRPV2 contributes to SU5416/hypoxia (SuHx)-induced ventricular remodeling and arrhythmias, and its possible mechanisms. Haemodynamic measurements, electrocardiogram, ventricular electrophysiological protocol, Wheat germ agglutinin (WGA) staining, hematoxylin and eosin (H&E) staining, Masson trichrome staining, immunofluorescence, real-time quantitative PCR (qPCR) and western blot were performed. Meanwhile, small interfering RNA (siRNA) for targeting TRPV2 or β-catenin was used to further verify the potential mechanism of TRPV2. In the SuHx-induced PH rat model, TRPV2 inhibitor tranilast significantly reduced mean pulmonary artery pressure (mPAP) and pulmonary vascular remodeling; relieved ventricular remodeling, myocardial fibrosis, and hypertrophy; shortened the prolongation of QT, QTc, Tpeak-Tend interval, effective refractory period (ERP) and action potential duration (APD); reduced susceptibility to ventricular fibrillation (VF). TRPV2 inhibition restored calcium homeostasis, attenuated ion channel and connexin remodeling (Kv4.3, Kv4.2, Kv1.5, Kir3.1, Kir3.4, KCNK3, Cx40 and Cx43), prevented autonomic dysfunction, reduced ventricular fibrosis, and inflammatory cytokines; In the hypoxia-induced H9c2 model, siRNA for targeting TRPV2 or β-catenin improved ion channel remodeling. TRPV2 inhibition suppressed the IGF1-mediated Wnt/β-catenin signaling pathway. Our data support TRPV2 inhibition prevents PH-induced right ventricular remodeling and VF susceptibility; TRPV2 can serve as a therapeutic target for PH-induced VF.