Myocardial infarction and apoptosis after myocardial ischemia and reperfusion - Role of the terminal complement components and inhibition by anti-C5 therapy

Article

关键词: MEMBRANE ATTACK COMPLEX;    ENDOTHELIAL VONWILLEBRAND-FACTOR;    PROTEIN GMP-140;    ISOLATED HEART;    CELL-SURFACE;    INJURY;    C5B-9;    RAT;    ADHESION;    C5A;   

DOI  :  10.1161/01.CIR.97.22.2259

来源: SCIE

【 摘 要 】

Background-Myocardial ischemia and reperfusion (MI/R)-induced tissue injury involves necrosis and apoptosis. However, the precise contribution of apoptosis to cell death, as well as the mechanism of apoptosis induction, has not been delineated. In this study, we sought to define the contribution of the activated terminal complement components to apoptosis and necrosis in a rat model of MI/R injury. Methods and Results-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 polymorphonuclear leukocytes (PMNs), whereas 16C had no complement inhibitor activity. A single dose (20 mg/kg IV) of 18A blocked > 80% of serum hemolytic activity for > 4 hours. Administration of 18A before myocardial ischemia (30 minutes) and reperfusion (4 hours) significantly reduced (91%) left ventricular free wall PMN infiltration compared with 16C treatment. Treatment with 18A 1 hour before ischemia or 5 minutes 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 of reperfusion. DNA ladders and DNA labeling leg, TUNEL assay) demonstrated a dramatic reduction in MI/R-induced apoptosis in 18A-treated compared with 16C-treated rats. Conclusions-Anti-C5 therapy in the setting of MI/R significantly inhibits cell apoptosis, necrosis, and PMN infiltration in the rat despite C3 deposition. We conclude that the terminal complement components C5a and C5b-9 are key mediators of tissue injury in MI/R.

【 授权许可】

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