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

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 (Pak2 ^cko ) or overexpression (Pak2 ^ctg ) 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 ²⁺ transient, measurements, demonstrated increased incidences of triggered ventricular arrhythmias, and prolonged action potential durations (APD) and altered Ca ²⁺ transients with increases in their beat‐to beat variations, in Pak2 ^cko 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 Pak2 ^cko 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.