Abstract 14275: Prokineticin Receptor -1 (pkr1) as a New Comer In Cardiac Progenitor Cell Conversion to Cardiovascular Cells
Epicardial resident progenitor cells are known to differentiate into vasculogenic cell type and cardiomyocytes during embryogenesis. Whether epicardium-derived progenitor cells (EPDCs) retain their plasticity after the birth remains unsolved. Prokineticins are angiogenic hormones that use G protein coupled receptors. Previous reports suggested that prokineticin receptor 1 (PKR1)signaling promotes angiogenesis and has cardio-protective effects in animal models of myocardial infarction. Global loss of PKR1 in mice does not interfere with cardiac development, however displays impaired capillary formation and EPDC proliferation, leading to cardiomyopathy. Here we showed that ablation of PKR1 specifically in the mice epicardium results in abnormalities in heart structure and function. Mutant hearts displayed low microvasculature and reduced ventricular wall at the neonatal stage, due to impaired EPDC proliferation and differentiation. Abnormal mitochondria, lipid accumulation in mutant cardiomyocytes leads to lower contractile response to dobutamine. Apoptosis was only observed in the adult mutant heart accompanied with ischemic and hypertrophic myocardium. Adult mutant hearts had also abnormal rythmicity and systolic functions detected by ECG and echocardiographic analyses. The survival rate in these mutant mice after the coronary ligation in a mouse model of myocardial infarction is dramatically reduced. Moreover, PKR1 signaling can induce differentiation of neonatal EPDC into endothelial, vascular smooth muscle cells and cardiomyocytes in vitro in the different experimental settings that was abolished in the neonatal EPDC isolated from mutant hearts. Cardiomyocyte proliferation and rytmicity were impaired when the neonatal cardiomyocytes were cultured in the conditional medium derived from mutant EPDCs.Our findings provide a mechanistic insight into the roles of PKR1 signaling in heart diseases controlling the maturation of EPDC proliferation and differentiation in a cell autonomous fashion and affecting cellular communications in a paracrine fashion.Our findings open stimulating prospects for specifically targeting PKR1 in cardioregenerative therapy
- © 2012 by American Heart Association, Inc.