Stress-Activated Kinase Mitogen-Activated Kinase Kinase-7 Governs Epigenetics of Cardiac Repolarization for Arrhythmia Prevention
| Autor: | Yatong Li, Shunyao Wang, Rongli Zhang, Wei Liu, Xudong Liao, Henggui Zhang, Ming Lei, Simon J. Castro, Min Zi, Mukesh K. Jain, Yong Ji, Xiuqin Zhang, Lukas Cyganek, Catherine B. Millar, Hoyee Tsui, Sanjoy K. Chowdhury, Rui-Ping Xiao, Elizabeth J. Cartwright, Sukhpal Prehar, Xin Wang, Holly A. Shiels, Mark R. Boyett, Kaomei Guan |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
MAP Kinase Kinase 7 Pharmacology Sudden death Epigenesis Genetic 03 medical and health sciences Kruppel-Like Factor 4 Mice Physiology (medical) Medicine FLNA Repolarization Animals Humans Myocytes Cardiac Regulation of gene expression biology business.industry Kinase Histone deacetylase 2 Arrhythmias Cardiac Potassium channel 3. Good health Rats 030104 developmental biology Mitogen-activated protein kinase Cancer research biology.protein Cardiology and Cardiovascular Medicine business |
| Zdroj: | Circulation. 135(7) |
| ISSN: | 1524-4539 |
| Popis: | Background: Ventricular arrhythmia is a leading cause of cardiac mortality. Most antiarrhythmics present paradoxical proarrhythmic side effects, culminating in a greater risk of sudden death. Methods: We describe a new regulatory mechanism linking mitogen-activated kinase kinase-7 deficiency with increased arrhythmia vulnerability in hypertrophied and failing hearts using mouse models harboring mitogen-activated kinase kinase-7 knockout or overexpression. The human relevance of this arrhythmogenic mechanism is evaluated in human-induced pluripotent stem cell–derived cardiomyocytes. Therapeutic potentials by targeting this mechanism are explored in the mouse models and human-induced pluripotent stem cell–derived cardiomyocytes. Results: Mechanistically, hypertrophic stress dampens expression and phosphorylation of mitogen-activated kinase kinase-7. Such mitogen-activated kinase kinase-7 deficiency leaves histone deacetylase-2 unphosphorylated and filamin-A accumulated in the nucleus to form a complex with Krüppel-like factor-4. This complex leads to Krüppel-like factor-4 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 Krüppel-like factor-4/histone deacetylase-2/filamin-A complex with the histone deacetylase-2 inhibitor valproic acid restores K + channel expression and alleviates ventricular arrhythmias in pathologically remodeled hearts. Conclusions: Our findings unveil this new gene regulatory avenue as a new antiarrhythmic target where repurposing of the antiepileptic drug valproic acid as an antiarrhythmic is supported. |
| Databáze: | OpenAIRE |
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