MYOCARDIAL-INFARCTION AND APOPTOSIS AFTER MYOCARDIAL-ISCHEMIA AND REPERFUSION - ROLE OF THE TERMINAL COMPLEMENT COMPONENTS AND INHIBITION BY ANTI-C5 THERAPY

Background-Myocardial ischemia and reperfusion (MI/R)-induced tissue i njury involves necrosis and apoptosis. However, the precise contributi on of apoptosis to cell death, as well as the mechanism of apoptosis i nduction, has not been delineated. In this study, we sought to define the contribution of the activated terminal complement components to ap optosis and necrosis in a rat model of MI/R injury. Methods and Result s-Monoclonal antibodies (mAbs; 18A and 16C) raised against the rat C5 complement component bound to purified rat C5 (ELISA). 18A effectively blocked C56-9-mediated cell lysis and C5a-induced chemotaxis of rat p olymorphonuclear leukocytes (PMNs), whereas 16C had no complement inhi bitor activity. A single dose (20 mg/kg IV) of 18A blocked > 80% of se rum hemolytic activity for > 4 hours. Administration of 18A before myo cardial ischemia (30 minutes) and reperfusion (4 hours) significantly reduced (91%) left ventricular free wall PMN infiltration compared wit h 16C treatment. Treatment with 18A 1 hour before ischemia or 5 minute s before reperfusion significantly reduced infarct size compared with 16C treatment. A significant reduction in infarct size (42%) was also observed in 18A-treated rats after 30 minutes of ischemia and 7 days o f reperfusion. DNA ladders and DNA labeling leg, TUNEL assay) demonstr ated a dramatic reduction in MI/R-induced apoptosis in 18A-treated com pared with 16C-treated rats. Conclusions-Anti-C5 therapy in the settin g of MI/R significantly inhibits cell apoptosis, necrosis, and PMN inf iltration in the rat despite C3 deposition. We conclude that the termi nal complement components C5a and C5b-9 are key mediators of tissue in jury in MI/R.