Mitogen-activated protein kinase kinase4 deficiency in cardiomyocytes causes connexin 43 reduction a

• 作 者: Min Zi Sukhpal Prehar Aleksandr Mironov Ludwig Neyses Marti F.A.Bierhuize Mark R.Boyett Henggui Zhang Ming Lei Elizabeth J.Cartwright Xin Wang Tomomi E.Kimura Wei Liu Jiawei Jin Jonathan Higham Sanjay
• 机 构: Manchester Academic Health Sciences Centre,The University of Manchester,Manchester M13 9NT,UK
• 出 处: The 3rd Ion Channel Conference: Ion channels-Structure, Func
• 发表日期: 2011年3期
• 关键词: MKK4 Cx43 gene regulation ventricular arrhythmias

　　Connexin 43 (Cx43) is the predominant isoform of gap junction proteins in the working myocardium.In the heart, mitogen-activated protein (MAP) kinases are implicated in regulating Cx43 remodeling; however, their precise roles remain obscure.Mitogen-activated protein kinase kinase 4 (MKK4) is a critical component of the stress-activated MAP kinase signaling pathway.We have previously demonstrated that MKK4 antagonizes cardiomyocyte hypertrophy.Herein, we investigate the role of MKK4 in regulating Cx43 expression in cardiomyocytes.We found that knockdown of MKK4 expression or inhibition of its kinase activity in neonatal rat cardiomyocytes (NRCMs) significantly reduced phenylephrine-induced Cx43 expression.Furthermore, two activator protein-1 (AP-1) binding elements in the Cx43 promoter region were identified as being responsible for the MKK4-regulated Cx43 expression.Consistently, we also detected heterogeneously reduced Cx43 expression and attenuated zonula occludens-1 (ZO-1) content in the hearts of MKK4 cardiomyocyte-specific knockout mice (MKK4cko) following pressure overload.To test whether heterogeneously reduced Cx43 expression contributes to ventricular arrhythmic vulnerability, MKK4cko and control mice were subjected to pressure overload followed by programmed elcctrical stimulation (PES).6 of 13 MKK4cko mice, but none of the controls, developed ventricular tachycardia.Epicardial activation mapping recorded from the MKK4cko hypertrophied heart showed ventricular activation delay.Mathematical models have simulated that the spatially heterogeneous decrease in Cx43 causes slowed ventricular conduction and fragmented wave propagations leading to re-entrant excitations.Collectively, these data reveal a novel role for MKK4 in regulating Cx43 expression and preventing hypertrophy-associated arrhythmogenesis.