Stress-activated kinase MKK7 governs epigenetics of cardiac repolarization for arrhythmia prevention
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) deficien...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
American Heart Association
2016
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| _version_ | 1826276381101654016 |
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| author | Chowdhury, S Liu, W Zi, M Li, Y Wang, S Tsui, H Prehar, S Castro, S Zhang, H Ji, Y Zhang, X Xiao, R Zhang, R Lei, M Cyganek, L Guan, K Millar, C Liao, X Jain, M Boyett, M Cartwright, E Shiels, H Wang, X |
| author_facet | Chowdhury, S Liu, W Zi, M Li, Y Wang, S Tsui, H Prehar, S Castro, S Zhang, H Ji, Y Zhang, X Xiao, R Zhang, R Lei, M Cyganek, L Guan, K Millar, C Liao, X Jain, M Boyett, M Cartwright, E Shiels, H Wang, X |
| author_sort | Chowdhury, S |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T23:13:05Z |
| format | Journal article |
| id | oxford-uuid:662e21c5-37f6-4531-b9b7-7e2a93e2ae59 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:13:05Z |
| publishDate | 2016 |
| publisher | American Heart Association |
| record_format | dspace |
| spelling | oxford-uuid:662e21c5-37f6-4531-b9b7-7e2a93e2ae592022-03-26T18:30:12ZStress-activated kinase MKK7 governs epigenetics of cardiac repolarization for arrhythmia preventionJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:662e21c5-37f6-4531-b9b7-7e2a93e2ae59EnglishSymplectic Elements at OxfordAmerican Heart Association2016Chowdhury, SLiu, WZi, MLi, YWang, STsui, HPrehar, SCastro, SZhang, HJi, YZhang, XXiao, RZhang, RLei, MCyganek, LGuan, KMillar, CLiao, XJain, MBoyett, MCartwright, EShiels, HWang, XBACKGROUND: -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. |
| spellingShingle | Chowdhury, S Liu, W Zi, M Li, Y Wang, S Tsui, H Prehar, S Castro, S Zhang, H Ji, Y Zhang, X Xiao, R Zhang, R Lei, M Cyganek, L Guan, K Millar, C Liao, X Jain, M Boyett, M Cartwright, E Shiels, H Wang, X Stress-activated kinase MKK7 governs epigenetics of cardiac repolarization for arrhythmia prevention |
| title | Stress-activated kinase MKK7 governs epigenetics of cardiac repolarization for arrhythmia prevention |
| title_full | Stress-activated kinase MKK7 governs epigenetics of cardiac repolarization for arrhythmia prevention |
| title_fullStr | Stress-activated kinase MKK7 governs epigenetics of cardiac repolarization for arrhythmia prevention |
| title_full_unstemmed | Stress-activated kinase MKK7 governs epigenetics of cardiac repolarization for arrhythmia prevention |
| title_short | Stress-activated kinase MKK7 governs epigenetics of cardiac repolarization for arrhythmia prevention |
| title_sort | stress activated kinase mkk7 governs epigenetics of cardiac repolarization for arrhythmia prevention |
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