Stress-Activated Kinase MKK7 Governs Epigenetics of Cardiac Repolarization for Arrhythmia Prevention

Sanjoy K. Chowdhury, Wei Liu, Min Zi, Yatong Li, Shunyao Wang, Hoyee Tsui, Sukhpal Prehar, Simon Castro, Henggui Zhang, Yong Ji, Xiuqin Zhang, Ruiping Xiao, Rongli Zhang, Ming Lei, Lukas Cyganek, Kaomei Guan, Catherine B. Millar, Xudong Liao, Mukesh K. Jain, Mark R. BoyettElizabeth J. Cartwright, Holly A. Shiels, Xin Wang

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BACKGROUND—: Ventricular arrhythmia is a leading cause of cardiac mortality. Most antiarrhythmics present paradoxical pro-arrhythmic side effects, culminating in a greater risk of sudden death. METHODS—: We describe a new regulatory mechanism linking mitogen-activated kinase kinase-7 (MKK7) deficiency with increased arrhythmia vulnerability in hypertrophied and failing hearts using mouse models harbouring MKK7 knockout or overexpression. The human relevance of this arrhythmogenic mechanism is evaluated in human induced pluripotent stem cells-derived cardiomyocytes (iPSC-CMs). Therapeutic potentials by targeting this mechanism are explored in the mouse models and human iPSC-CMs. RESULTS—: Mechanistically, hypertrophic stress dampens expression and phosphorylation of MKK7. Such MKK7 deficiency leaves histone deacetylase-2 (HDAC2) unphosphorylated and filamin-A (FLNA) accumulated in the nucleus to form a complex with Krϋppel-like factor-4 (KLF4). This complex leads to KLF4 disassociation from the promoter regions of multiple key potassium channel genes (Kv4.2, KChIP2, Kv1.5, ERG1 and Kir6.2) and reduction of their transcript levels. Consequent repolarization delays result in ventricular arrhythmias. Therapeutically, targeting the repressive function of the KLF4/HDAC2/FLNA complex with the HDAC2 inhibitor Valproic acid (VPA) restores K channel expression and alleviates ventricular arrhythmias in pathologically remodelled hearts. CONCLUSIONS—: Our findings unveil this new gene regulatory avenue as a new anti-arrhythmic target where repurposing of anti-epileptic drug VPA as an antiarrhythmic is supported.

Original languageEnglish
Pages (from-to)683-699
Number of pages17
Issue number7
Early online date29 Nov 2016
Publication statusPublished - 2017

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