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

Sanjoy K Chowdhury1, Wei Liu1, Min Zi1

  • 1From 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.).

Circulation
|December 1, 2016
PubMed
Abstract

Insights

Mitogen-activated kinase kinase-7 deficiency increases ventricular arrhythmia risk by disrupting potassium channel gene expression. Targeting this pathway with valproic acid may offer a new antiarrhythmic therapy.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Genetics

Background:

  • Ventricular arrhythmia is a major cause of cardiac death.
  • Existing antiarrhythmics often have proarrhythmic side effects, increasing sudden death risk.

Purpose of the Study:

  • To investigate a novel regulatory mechanism linking mitogen-activated kinase kinase-7 (MKK7) deficiency to arrhythmia vulnerability in heart failure.
  • To explore therapeutic strategies targeting this mechanism.

Main Methods:

  • Utilized mouse models with MKK7 knockout or overexpression to study arrhythmia mechanisms in hypertrophied and failing hearts.
  • Evaluated the human relevance using human-induced pluripotent stem cell-derived cardiomyocytes.
  • Tested therapeutic interventions in both mouse models and human cells.

Main Results:

  • Hypertrophic stress reduces MKK7 expression and phosphorylation, leading to an unphosphorylated histone deacetylase-2 and nuclear accumulation of filamin-A.
  • This complex disrupts Krüppel-like factor-4 binding to potassium channel gene promoters, reducing channel expression and causing repolarization delays.
  • Valproic acid, a histone deacetylase-2 inhibitor, restored potassium channel expression and reduced ventricular arrhythmias in pathological hearts.

Conclusions:

  • Identified a new gene regulatory pathway involving MKK7, HDAC2, FLNA, and KLF4 as a critical determinant of ventricular arrhythmia susceptibility.
  • Repurposing valproic acid as an antiarrhythmic agent is supported by these findings for treating pathological ventricular arrhythmias.
Keywords:
arrhythmias, cardiacgene expression regulationheart failurepharmaceutical preparationstherapeutics

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