title: Anti-apoptotic role for C1 inhibitor in ischemia/reperfusion-induced myocardial cell injury.
abstract: Complement activation augments myocardial cell injury and apoptosis during ischemia/reperfusion (I/R), whereas complement system inhibition with C1 inhibitor (C1INH), a serine protease inhibitor, exerts markedly cardioprotective effects. Our recent data demonstrate that C1INH prevents vascular endothelial cell apoptosis and a "modified" form of the reactive center loop-cleaved, inactive C1INH (iC1INH) plays an anti-inflammatory role in endotoxin shock. The aim of this study was to determine whether C1INH protects against myocardial cell injury via an anti-apoptotic activity or anti-inflammatory effect. In a rat model of acute myocardial infarction (AMI) induced by I/R, administration of C1INH protected against cardiomyocytic apoptosis via normalization of ratio of the Bcl-2/Bax expression in the myocardial infarct area. C1INH improved parameters of cardiac function and hemodynamics and reduced myocardial infarct size (MIS). In addition, myocardial and blood myeloperoxidase (MPO) activity, a marker of neutrophil infiltration, was decreased by treatment of C1INH. In cultured H9c2 rat cardiomyocytic cells, C1INH blocked hypoxia/reoxygenation-induced apoptosis in the absence of sera associated with inhibition of cytochrome c translocation and suppression of caspase-3 activation. The proportion of Bcl-2/Bax expression induced by hypoxia/reoxygenation was reversed by C1INH. Importantly, iC1INH also revealed these similar effects, indicating that C1INH has a direct anti-apoptotic activity. Therefore, these studies support the hypothesis that C1INH, in addition to inhibition of activation of the complement and contact systems, improves outcome in I/R-mediated myocardial cell injury via an anti-apoptotic activity independent of serine protease inhibitory activity.
authors.affiliation: Department of Cardiology, Renmin Hospital, Wuhan University School of Medicine, Wuhan, Hubei, PR China.
authors.forename: Jinrong
authors.initials: J
authors.lastname: Fu
authors.forename: Guosheng
authors.initials: G
authors.lastname: Lin
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Wu
authors.forename: Bin
authors.initials: B
authors.lastname: Ceng
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Wu
authors.forename: Gong
authors.initials: G
authors.lastname: Liang
authors.forename: Gangjian
authors.initials: G
authors.lastname: Qin
authors.forename: Jinan
authors.initials: J
authors.lastname: Li
authors.forename: Isaac
authors.initials: I
authors.lastname: Chiu
authors.forename: Dongxu
authors.initials: D
authors.lastname: Liu
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D017209:Apoptosis; D001692:Biological Transport; D002316:Cardiotonic Agents; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003172:Complement C1 / Q000037:antagonists & inhibitors*; D050718:Complement C1 Inhibitor Protein / Q000378:metabolism / Q000502:physiology*; D004789:Enzyme Activation; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D009195:Peroxidase / Q000097:blood / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury
chemical_list: D000893:Anti-Inflammatory Agents; D002316:Cardiotonic Agents; D003172:Complement C1; D050718:Complement C1 Inhibitor Protein; D009195:Peroxidase; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases