Abstract 226: p21-activated kinase-1 (Pak1) Mediates Exercise-induced Cardiac Remodeling Through Calcineurin Signaling

Abstract

Aims: Despite its known cardiovascular benefits, the intracellular signaling mechanisms underlying physiological cardiac growth remain poorly understood. Therefore, the purpose of this study was to investigate a novel role of p21-activated-kinase-1 (Pak1) in the regulation of exercise-induced cardiac hypertrophy. Methods & Results: Wild-type and Pak1 KO mice were subjected to six weeks of treadmill endurance exercise-training (ex-training). Cardiac function was assessed via echocardiography, in situ hemodynamics, and the pCa-force relations in skinned fiber preparations at baseline and at the end of the training regimen. Post-translational modifications to the sarcomeric proteins and expression levels of calcium-regulating proteins were also assessed following ex-training. HW/TL and echocardiography data revealed there was marked hypertrophy following ex-training in the WT mice, which was not evident in the KO mice. Additionally, following ex-training, WT mice demonstrated an increase in cardiac contractility, myofilament calcium sensitivity, phosphorylation of cMyBP-C, cTNT, and TM compared to KO mice. The improvement in contractility with ex-training was accompanied by increased protein levels of SERCA2a and calcineurin along with increased phosphorylation of phospholamban. Conclusions: Our data suggest that Pak1 is essential for adaptive physiological cardiac remodeling and support previous evidence that demonstrate Pak1 signaling is important for cardiac growth and survival.