2. Academic Validation
  3. P21-Activated Kinase 2 as a Novel Target for Ventricular Tachyarrhythmias Associated with Cardiac Adrenergic Stress and Hypertrophy

P21-Activated Kinase 2 as a Novel Target for Ventricular Tachyarrhythmias Associated with Cardiac Adrenergic Stress and Hypertrophy

  • Adv Sci (Weinh). 2025 Mar 11:e2411987. doi: 10.1002/advs.202411987.
Tao Li 1 2,  Ting Liu 1,  Yan Wang 1,  Yangpeng Li 1 2,  Leiying Liu 1,  James Bae 3,  Yu He 3,  Xian Luo 1 2,  Zhu Liu 1 2,  Tangting Chen 1,  Xianhong Ou 1,  Dan Zhang 1,  Huan Lan 1,  Juyi Wan 2,  Yan Wei 1,  Fang Zhao 3 4,  Xin Wang 5,  Tao Li 6,  Christopher L-H Huang 7 8,  Chunxiang Zhang 1 2,  Ming Lei 1 3,  Xiaoqiu Tan 1 2 9
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Cardiology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, 646000, China.
  • 3 Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK.
  • 4 Department of Cardiology, Zhongnan Hospital of Wuhan University, East Lake Road 169, Wuhan, 430071, China.
  • 5 Faculty of Biology, Medicine and Health, The University of Manchester, Dover Street, Manchester, M13 9GB, UK.
  • 6 Laboratory of Mitochondria and Metabolism, West China Hospital of Sichuan University, Chengdu, 610041, China.
  • 7 Physiological Laboratory, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK.
  • 8 Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QW, UK.
  • 9 Department of Physiology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, 646000, China.
PMID: 40068092 DOI: 10.1002/advs.202411987
Abstract

Ventricular arrhythmias associated with cardiac adrenergic stress and hypertrophy pose a significant clinical challenge. We explored ventricular anti-arrhythmic effects of P21-activated kinase 2 (PAK2), comparing in vivo and ex vivo cardiomyocyte-specific PAK2 knockout (PAK2cko) or overexpression (PAK2ctg) 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 CA2+ transient, measurements, demonstrated increased incidences of triggered ventricular arrhythmias, and prolonged action potential durations (APD) and altered CA2+ transients with increases in their beat-to beat variations, in PAK2cko hearts. Electron microscopic, proteomic, and molecular biological methods revealed a mitochondrial localization of stress-related proteins on proteomic and phosphoproteomic analyses, particularly in TAC stressed PAK2cko mice. They further yielded accompanying evidence for mitochondrial oxidative stress, increased Reactive Oxygen Species (ROS) biosynthesis, reduced mitochondrial complexes I-V, 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-arrhythmic targets.

Keywords

Ca2+ handling; NADPH oxidase; P21‐activated kinase 2; cardiac arrhythmia; mitochondrial oxidative stress.

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