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We explored ventricular anti\u2010arrhythmic effects of P21\u2010activated kinase 2 (Pak2), comparing in vivo and ex vivo cardiomyocyte\u2010specific Pak2 knockout (Pak2\n                    <jats:sup>cko<\/jats:sup>\n                    ) or overexpression (Pak2\n                    <jats:sup>ctg<\/jats:sup>\n                    ) murine models, under conditions of acute adrenergic stress, and hypertrophy following chronic transverse aortic constriction (TAC). Pak2 was downregulated 5 weeks following the latter TAC challenge. Cellular physiological, optical action potential and Ca\n                    <jats:sup>2+<\/jats:sup>\n                    transient, measurements, demonstrated increased incidences of triggered ventricular arrhythmias, and prolonged action potential durations (APD) and altered Ca\n                    <jats:sup>2+<\/jats:sup>\n                    transients with increases in their beat\u2010to beat variations, in Pak2\n                    <jats:sup>cko<\/jats:sup>\n                    hearts. Electron microscopic, proteomic, and molecular biological methods revealed a mitochondrial localization of stress\u2010related proteins on proteomic and phosphoproteomic analyses, particularly in TAC stressed Pak2\n                    <jats:sup>cko<\/jats:sup>\n                    mice. They further yielded accompanying evidence for mitochondrial oxidative stress, increased reactive oxygen species (ROS) biosynthesis, reduced mitochondrial complexes I\u2010V, diminished ATP synthesis and elevated NADPH oxidase 4 (NOX4) levels. Pak2 overexpression and the novel Pak2 activator JB2019A ameliorated these effects, enhanced cardiac function and decreased the frequencies of triggered ventricular arrhythmias. Pak2 activation thus protects against ventricular arrhythmia associated with cardiac stress and hypertrophy, through unique mechanisms offering potential novel therapeutic anti\u2010arrhythmic targets.\n                  <\/jats:p>","DOI":"10.1002\/advs.202411987","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T15:51:06Z","timestamp":1741708266000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["P21\u2010Activated Kinase 2 as a Novel Target for Ventricular Tachyarrhythmias Associated with Cardiac Adrenergic Stress and Hypertrophy"],"prefix":"10.1002","volume":"12","author":[{"given":"Tao","family":"Li","sequence":"first","affiliation":[{"name":"Key Laboratory of Medical Electrophysiology of the Ministry of Education Medical Electrophysiological Key Laboratory of Sichuan Province Institute of Cardiovascular Research Southwest Medical University  Luzhou Sichuan 646000 China"},{"name":"Department of Cardiology The Affiliated Hospital Southwest Medical University  Luzhou Sichuan 646000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Electrophysiology of the Ministry of Education Medical Electrophysiological Key Laboratory of Sichuan Province Institute of Cardiovascular Research Southwest Medical University  Luzhou Sichuan 646000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Electrophysiology of the Ministry of Education Medical Electrophysiological Key Laboratory of Sichuan Province Institute of Cardiovascular Research Southwest Medical University  Luzhou Sichuan 646000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangpeng","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Electrophysiology of the Ministry of Education Medical Electrophysiological Key Laboratory of Sichuan Province Institute of Cardiovascular Research Southwest Medical University  Luzhou Sichuan 646000 China"},{"name":"Department of Cardiology The Affiliated Hospital Southwest Medical University  Luzhou Sichuan 646000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leiying","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Electrophysiology of the Ministry of Education Medical Electrophysiological Key Laboratory of Sichuan Province Institute of Cardiovascular Research Southwest Medical University  Luzhou Sichuan 646000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Bae","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of Oxford  Mansfield Road Oxford OX1 3QT 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