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Circulation. 2017 Feb 14;135(7):683-699. doi: 10.1161/CIRCULATIONAHA.116.022941. Epub 2016 Nov 29.

Stress-Activated Kinase Mitogen-Activated Kinase Kinase-7 Governs Epigenetics of Cardiac Repolarization for Arrhythmia Prevention.

Author information

1
From Faculty of Biology, Medicine and Health (S.K.C., W.L., M.Z., Y.L., S.W., H.T., S.P., C.B.M., M.R.B., E.J.C., H.A.S., X.W.) and School of Physics and Astronomy (S.C., H.Z.), University of Manchester, United Kingdom; Atherosclerosis Research Centre, Nanjing Medical University, Jiangsu, China (Y.J.); Institute of Molecular Medicine, Peking University, Beijing, China (X.Z., R.X.); Case Cardiovascular Research Institute, Case Western Reserve University, Cleveland, OH (R.Z., X.L., M.K.J.); Department of Pharmacology, University of Oxford, United Kingdom (M.L.); and Department of Cardiology and Pneumology, University Medical Center Göttingen, Germany (L.C., K.G.).
2
From Faculty of Biology, Medicine and Health (S.K.C., W.L., M.Z., Y.L., S.W., H.T., S.P., C.B.M., M.R.B., E.J.C., H.A.S., X.W.) and School of Physics and Astronomy (S.C., H.Z.), University of Manchester, United Kingdom; Atherosclerosis Research Centre, Nanjing Medical University, Jiangsu, China (Y.J.); Institute of Molecular Medicine, Peking University, Beijing, China (X.Z., R.X.); Case Cardiovascular Research Institute, Case Western Reserve University, Cleveland, OH (R.Z., X.L., M.K.J.); Department of Pharmacology, University of Oxford, United Kingdom (M.L.); and Department of Cardiology and Pneumology, University Medical Center Göttingen, Germany (L.C., K.G.). xin.wang@manchester.ac.uk.

Abstract

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.

KEYWORDS:

arrhythmias, cardiac; gene expression regulation; heart failure; pharmaceutical preparations; therapeutics

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