{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T21:07:18Z","timestamp":1790543238347,"version":"4.1.0"},"reference-count":39,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2017,2,14]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>Ventricular arrhythmia is a leading cause of cardiac mortality. Most antiarrhythmics present paradoxical proarrhythmic side effects, culminating in a greater risk of sudden death.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>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\u2013derived cardiomyocytes. Therapeutic potentials by targeting this mechanism are explored in the mouse models and human-induced pluripotent stem cell\u2013derived cardiomyocytes.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              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 Kr\u00fcppel-like factor-4. This complex leads to Kr\u00fcppel-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 Kr\u00fcppel-like factor-4\/histone deacetylase-2\/filamin-A complex with the histone deacetylase-2 inhibitor valproic acid restores K\n              <jats:sup>+<\/jats:sup>\n              channel expression and alleviates ventricular arrhythmias in pathologically remodeled hearts.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.116.022941","type":"journal-article","created":{"date-parts":[[2016,11,30]],"date-time":"2016-11-30T04:38:18Z","timestamp":1480480698000},"page":"683-699","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":20,"title":["Stress-Activated Kinase Mitogen-Activated Kinase Kinase-7 Governs Epigenetics of Cardiac Repolarization for Arrhythmia Prevention"],"prefix":"10.1161","volume":"135","author":[{"given":"Sanjoy K.","family":"Chowdhury","sequence":"first","affiliation":[{"name":"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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Liu","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Zi","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yatong","family":"Li","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunyao","family":"Wang","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoyee","family":"Tsui","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sukhpal","family":"Prehar","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Castro","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henggui","family":"Zhang","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Ji","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuqin","family":"Zhang","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruiping","family":"Xiao","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongli","family":"Zhang","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Lei","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukas","family":"Cyganek","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaomei","family":"Guan","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine B.","family":"Millar","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xudong","family":"Liao","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mukesh K.","family":"Jain","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark R.","family":"Boyett","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth J.","family":"Cartwright","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly A.","family":"Shiels","sequence":"additional","affiliation":[{"name":"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..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Wang","sequence":"additional","affiliation":[{"name":"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; 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