title: Extracellular matrix protein CCN1 regulates cardiomyocyte apoptosis in mice with stress-induced cardiac injury.
abstract: OBJECTIVE
  Expression of extracellular matrix protein CCN1 is induced in end-stage ischaemic cardiomyopathy in humans, and after cardiac ischaemia and reperfusion in experimental animal models. Despite its well-documented angiogenic activities, CCN1 increases the cytotoxicities of the tumour necrosis factor family cytokines, which promotes apoptosis in fibroblasts. We aimed to determine the physiological function of CCN1 in an injured heart.
  
  
  RESULTS
  To assess the function of CCN1 in vivo, knock-in mice carrying the apoptosis-defective mutant allele Ccn1-dm were tested in an isoproterenol (ISO)-induced myocardial injury model (100 mg/kg/day of sc injected ISO for 5 days). Compared with wild-type mice, Ccn1(dm/dm) mice were remarkably resistant to ISO-induced cardiac injury; they showed no post-treatment cardiomyocyte apoptosis or myocardial tissue damage. ISO cardiotoxicity was dependent on Fas ligand (FasL) and its downstream signalling. Using primary cultures of cardiomyocytes isolated from rats, we demonstrated that CCN1 sensitized FasL-mediated apoptosis by engaging its cell-surface receptor integrin α6β1 and up-regulating intracellular reactive oxygen species (ROS), which activated mitogen-activated protein kinase p38, and increased cell-surface Fas expression.
  
  
  CONCLUSIONS
  CCN1 is a critical pathophysiological regulator that mediates cardiomyocyte apoptosis during work-overload-induced cardiac injury. CCN1 increases cellular susceptibility to Fas-induced apoptosis by increasing ROS and cell-surface Fas expression.
authors: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors: Pei-Ling
authors: PL
authors: Hsu
authors: Bor-Chyuan
authors: BC
authors: Su
authors: Qian-Yu
authors: QY
authors: Kuok
authors: Fan-E
authors: FE
authors: Mo
mesh_terms: D000818:Animals; D017209:Apoptosis; D055515:Cysteine-Rich Protein 61 / Q000502:physiology*; D053222:Fas Ligand Protein / Q000502:physiology; D039121:Integrin alpha6beta1 / Q000502:physiology; D007545:Isoproterenol / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: D055515:Cysteine-Rich Protein 61; D053222:Fas Ligand Protein; D039121:Integrin alpha6beta1; D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases; D007545:Isoproterenol