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

被引：17

作者：

Chowdhury, Sanjoy K. ^{[1
]}

Liu, Wei ^{[1
]}

Zi, Min ^{[1
]}

Li, Yatong ^{[1
]}

Wang, Shunyao ^{[1
]}

Tsui, Hoyee ^{[1
]}

Prehar, Sukhpal ^{[1
]}

Castro, Simon ^{[2
]}

Zhang, Henggui ^{[2
]}

Ji, Yong ^{[3
]}

Zhang, Xiuqin ^{[4
]}

Xiao, Ruiping ^{[4
]}

Zhang, Rongli ^{[5
]}

Lei, Ming ^{[6
]}

Cyganek, Lukas ^{[7
]}

Guan, Kaomei ^{[7
]}

Millar, Catherine B. ^{[1
]}

Liao, Xudong ^{[5
]}

Jain, Mukesh K. ^{[5
]}

Boyett, Mark R. ^{[1
]}

Cartwright, Elizabeth J. ^{[1
]}

Shiels, Holly A. ^{[1
]}

Wang, Xin ^{[1
]}

机构：

[1] Univ Manchester, Fac Biol Med & Hlth, Michael Smith Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England

[2] Univ Manchester, Sch Phys & Astron, Manchester, Lancs, England

[3] Nanjing Med Univ, Atherosclerosis Res Ctr, Nanjing, Jiangsu, Peoples R China

[4] Peking Univ, Inst Mol Med, Beijing, Peoples R China

[5] Case Western Reserve Univ, Case Cardiovasc Res Inst, Cleveland, OH 44106 USA

[6] Univ Oxford, Dept Pharmacol, Oxford, England

[7] Univ Med Ctr Gottingen, Dept Cardiol & Pneumol, Gottingen, Germany

来源：

CIRCULATION | 2017年 / 135卷 / 07期

基金：

英国工程与自然科学研究理事会; 英国医学研究理事会;

关键词：

arrhythmias; cardiac; gene expression regulation; heart failure; pharmaceutical preparations; therapeutics; HISTONE DEACETYLASE INHIBITOR; VENTRICULAR-ARRHYTHMIAS; CHANNEL FUNCTION; HEART-FAILURE; SUDDEN-DEATH; HYPERTROPHY; PROLONGATION; MECHANISMS; VALPROATE; THERAPY;

D O I：

10.1161/CIRCULATIONAHA.116.022941

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

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 Kruppel-like factor-4. This complex leads to Kruppel-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 Kruppel-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.

引用

页码：683 / 699

页数：17

共 39 条

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