TRPV4 blockade suppresses atrial fibrillation in sterile pericarditis rats.

Jie Liao,Lei Chen,Kai Lu,Cheng Qian,Shaoshao Zhang,Qince Li,Ning Zhao,Qian Dong,Qiongfeng Wu,Yimei Du,Zhaoyang Zhao

doi:10.1172/jci.insight.137528

Abstract

Atrial fibrillation (AF) commonly occurs after surgery and is associated with atrial remodeling. TRPV4 is functionally expressed in the heart, and its activation affects cardiac structure and functions. We hypothesized that TRPV4 blockade alleviates atrial remodeling and reduces AF induction in sterile pericarditis (SP) rats. TRPV4 antagonist GSK2193874 or vehicle was orally administered 1 day before pericardiotomy. AF susceptibility and atrial function were assessed using in vivo electrophysiology, ex vivo optical mapping, patch clamp, and molecular biology on day 3 after surgery. TRPV4 expression increased in the atria of SP rats and patients with AF. GSK2193874 significantly reduced AF vulnerability in vivo and the frequency of atrial ectopy and AF with a reentrant pattern ex vivo. Mechanistically, GSK2193874 reversed the abnormal action potential duration (APD) prolongation in atrial myocytes through the regulation of voltage-gated K+ currents (IK); reduced the activation of atrial fibroblasts by inhibiting P38, AKT, and STAT3 pathways; and alleviated the infiltration of immune cells. Our results reveal that TRPV4 blockade prevented abnormal changes in atrial myocyte electrophysiology and ameliorated atrial fibrosis and inflammation in SP rats; therefore, it might be a promising strategy to treat AF, particularly postoperative AF.

Highlights

Atrial fibrillation (AF) is the most common sustained arrhythmia observed in clinical settings and often occurs after cardiac surgery [1]
Positive immunoreaction for Transient receptor potential vanilloid 4 (TRPV4) was confined to the nuclear zone in sham-operated rats, but the signal was stronger and clearly visible on the outside of the nucleus on day 3. These results suggest that the expression of TRPV4 was upregulated in the atria of sterile pericarditis (SP) rats
TRPV4 immunostaining was found in both atrial myocytes and fibroblasts, and its staining intensity was much stronger in the vehicle group than the sham group

Summary

Introduction

Atrial fibrillation (AF) is the most common sustained arrhythmia observed in clinical settings and often occurs after cardiac surgery [1]. Atrial remodeling induced by inflammatory profibrotic signals plays a critical role in the pathogenesis of AF [2]. Cardiac surgery stimulates inflammatory profibrotic signals and subsequently leads to enhanced vulnerability to AF in patients [3] as well as in the sterile pericarditis (SP) animal model, a well-established model of human postoperative AF [4,5,6]. TRPV4 is expressed in cardiomyocytes, fibroblasts, endothelial cells, and smooth muscle cells, as well as in tissues such as the lung, heart, liver, and skin [8]. TRPV4 activation leads to mPTP opening and cell apoptosis during hypoxia/reoxygenation [10]. We hypothesize that the blockade of TRPV4 alleviates atrial remodeling and reduces the induction of AF

Methods

Results

Discussion

Conclusion