P21-Activated Kinase-1 Signaling in Myocardial Hypertrophy, Ischemic Heart Disease and Remodeling

P21-Activated Kinase-1 Signaling in Myocardial Hypertrophy, Ischemic Heart Disease and Remodeling Domenico M. Taglieri, M.D., Ph.D. Department of Physiology and Biophysics University of Illinois at Chicago Chicago, Illinois (2011) Dissertation Chairperson: Dr. Jesus Garcia-Martinez The role of p21-activated kinase-1 (Pak1) in the development of stress-induced cardiac growth, ischemic injury, and post-ischemic cardiac remodeling was explored. We determined the effects of ablation of the Pak1 gene on the response of the myocardium to chronic stress of isoproterenol (ISO) administration. In a separate set of experiments, we determined the effect of Pak1 on acute global cardiac ischemic/reperfusion (I/R) injury. In yet another set of experiments, we determined the effect of Pak1 on long-term myocardial remodeling after ligation of the left anterior descending coronary artery for 10 weeks. Results indicate that active Pak1 is a natural inhibitor of Erk1/2 and a novel anti-hypertrophic signaling molecule upstream of PP2A. Pak1-KO hearts have reduced recovery of myocardial performance after acute global I/R injury concomitant with changes in troponin-T and MLC2 phosphorylation. In a separate set of experiments, compared to WT controls, in vivo hearts from Pak1-KO mice subjected to ligation of the left anterior descending coronary artery for 10 weeks develop significantly reduced global systolic and diastolic function as assessed by transthoracic echocardiography, as well as significantly reduced compensatory left ventricular mass, indicative of impaired cardiac remodeling. At the end of the 10 weeks, mortality was significantly higher in the Pak1-null mice group versus WT. Pak1 signaling is protective in multiple disease models (isoproterenol-induced hypertrophy, acute global I/R injury, and left anterior descending coronary artery ligation). Our studies provide a novel target for future investigations of the molecular signaling during stress.