title: Cardioprotective effects of selective inhibition of the two complement activation pathways in myocardial ischemia and reperfusion injury.
abstract: The complement (C) system-mediated neutrophil activation, adhesion to the coronary endothelium and accumulation into cardiac tissue are key steps in the pathogenesis of myocardial ischemia-reperfusion (MI/R) injury. We examined the differential role of the classical and the alternative complement pathway in MI/R injury in vivo. Rats were subjected to 20 min of myocardial ischemia followed by 24 h of reperfusion. Either a classical pathway inhibitor [C1 esterase inhibitor (C1-INH) (15 mg/kg)] or an alternative pathway inhibitor soluble complement receptor 1 (sCR1)[des-LHR-A](15 mg/kg) or their vehicle were administered intravenously 1 min prior to reperfusion, and myocardial necrosis (creatine kinase loss) and neutrophil accumulation, cardiac myeloperoxidase activity, were examined. C1-INH significantly attenuated cardiac creatine kinase loss compared to MI/R rats given only vehicle (p < 0.05) 24 h after reperfusion. An alternative pathway inhibitor, sCR1 [des-LHR-A] attenuated myocardial injury to a lesser extent, although it was not significantly different from the value for C1-INH or vehicle. Besides cardiac myeloperoxidase activity, the ischemic cardiac tissue was significantly attenuated by both C1-INH and sCR1[desLHR-A] (p < 0.05 vs. vehicle). Both the classical and alternative pathways may contribute to MI/R injury via a neutrophil-dependent mechanism in vivo. Selective inhibition of the classical pathway of complement activation seems to be slightly more effective in limiting necrotic MI/R injury than the selective alternative pathway inhibition in this 24 h model of reperfusion injury, but equal doses of each inhibitor attenuated neutrophil accumulation.
authors: Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA.
authors: T
authors: T
authors: Murohara
authors: J P
authors: JP
authors: Guo
authors: J A
authors: JA
authors: Delyani
authors: A M
authors: AM
authors: Lefer
mesh_terms: D000818:Animals; D003167:Complement Activation; D003170:Complement Pathway, Alternative; D003171:Complement Pathway, Classical; D003402:Creatine Kinase / Q000378:metabolism; D008297:Male; D017202:Myocardial Ischemia / Q000201:enzymology*; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000201:enzymology*
chemical_list: D009195:Peroxidase; D003402:Creatine Kinase