title: CCN1 enables Fas ligand-induced apoptosis in cardiomyoblast H9c2 cells by disrupting caspase inhibitor XIAP.
abstract: Cell proliferation from pre-existing cardiomyocytes is a major source of cells for normal mammalian myocardial renewal or for regeneration after myocardial injury. These proliferative cardiomyocytes may act differently from the postmitotic cardiomyocytes in a stressed heart. Extracellular matrix molecule CCN1 is produced to promote Fas ligand (FasL)-induced cardiomyocyte apoptosis in mice with stress-induced cardiac injury. We aimed to investigate the effect of CCN1 on the proliferative cardiomyocytes. We used rat embryonic cardiomyoblast H9c2 cells to study the cardiotoxicity of CCN1. We found that FasL dose-dependently increased the X-linked inhibitor of apoptosis protein (XIAP) levels to prevent the progression of apoptosis in H9c2 cells. CCN1, though it did not induce apoptosis by itself, sensitized H9c2 cells to FasL-induced apoptosis. CCN1 functions by engaging its cell-surface receptor integrin α6β1 and elevating reactive oxygen species levels, which leads to mitogen-activated protein kinase p38 activation, cytosolic Bax translocation to mitochondria, and the release of mitochondrial Smac and HtrA2 to cytosol. These elevated cytosolic Smac and HtrA2 dismantle the inhibition of XIAP, thereby facilitating the activation of caspase-3 and the apoptosis-induced by FasL. In summary, we demonstrated a novel mechanism underlying the resistance of cardiomyoblasts to FasL-induced apoptosis, and the pro-apoptotic function of CCN1 by disrupting this resistance.
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Bor-Chyuan
authors.initials: BC
authors.lastname: Su
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Electronic address: femo@mail.ncku.edu.tw.
authors.forename: Fan-E
authors.initials: FE
authors.lastname: Mo
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D055515:Cysteine-Rich Protein 61 / Q000502:physiology*; D053222:Fas Ligand Protein / Q000502:physiology*; D039121:Integrin alpha6beta1 / Q000378:metabolism; D008929:Mitochondria, Heart / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D032386:Myoblasts, Cardiac / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D021381:Protein Transport; D016601:RNA-Binding Proteins / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D000068103:Serine-Arginine Splicing Factors; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C494828:Bax protein, rat; C501849:CCN1 protein, rat; D002352:Carrier Proteins; D055515:Cysteine-Rich Protein 61; C489013:DIABLO protein, rat; D053222:Fas Ligand Protein; C491898:Fas protein, rat; D039121:Integrin alpha6beta1; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; C490770:Tra2b protein, rat; D051636:X-Linked Inhibitor of Apoptosis Protein; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; D000068103:Serine-Arginine Splicing Factors; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Apoptosis; CCN1; Cardiomyoblasts; Fas ligand; Mitochondria; XIAP