Extracellular Matrix Protein CCN1 Regulates Apoptosis and Autophagy in Cardiomyocytes

Abstract

Mammalian hearts are with limited regenerative capacity Recent studies demonstrated that a small portion of resident cardiomyocytes possesses proliferative ability which is the major source of cardiomyocyte renewal in myocardial homeostasis and in myocardial injury Understanding the regulation of cell apoptosis on the postmitotic and proliferative cardiomyocytes can provide insights and leads to discover potential therapeutic targets for myocardial injury Among the physiological regulators Fas/Fas ligand (FasL) are implicated in various cardiac pathological conditions; however Fas agonistic antibody Jo2 is unable to induce cardiomyocyte apoptosis in vivo suggesting that additional factors are required in the regulation of Fas-mediated apoptosis Extracellular protein CCN1 has been demonstrated to promote cytotoxicity of FasL in human skin fibroblasts In addition CCN1 is induced in a variety of cardiac pathologies We hypothesized that CCN1 and FasL may coordinatively regulate cardiomyocyte survival We found that CCN1 and FasL synergized to induce primary cardiomyocyte (postmitotic cardiomyocyte) and H9c2 cardiomyoblast (proliferative cardiomyocyte) apoptosis via distinct mechanisms CCN1 sensitized primary cardiomyocytes to FasL-induced apoptosis through inducing ROS and the p38-dependent elevation of cell surface Fas In contrast CCN1 synergized with FasL in H9c2 cells via increasing cytosolic Smac and HtrA2 to counteract anti-apoptotic XIAP Moreover we also found that adaptive autophagy was induced in H9c2 cells to restrict the cardiotoxicity of CCN1 In summary CCN1 plays a detrimental role in cardiac injury by sensitizing cardiomyocytes to FasL-induced apoptosis CCN1 may represent a new therapeutic target for stressed-induced myocardial injury

Date of Award	2014 Aug 11
Original language	English
Supervisor	Fan-E Mo (Supervisor)