Novel small molecule inhibitor of C1s exerts cardioprotective effects in ischemia-reperfusion injury in rabbits

被引:65
作者
Buerke, M
Schwertz, H
Seitz, W
Meyer, J
Darius, H
机构
[1] Johannes Gutenberg Univ Mainz, Dept Med 2, D-55101 Mainz, Germany
[2] BASF Pharma, Ludwigshafen, Germany
关键词
D O I
10.4049/jimmunol.167.9.5375
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Myocardial ischemia-reperfusion injury can be related to complement activation with generation of chemotactic agents, adhesion molecule expression, release of cytokines and oxygen-derived free radicals, and subsequent neutrophil accumulation. In the present study the cardioprotective effects of a novel highly selective small molecule C1s inhibitor (C1s-INH-248, Knoll) were examined in a rabbit model of myocardial Ischemia (1) and reperfusion (R; i.e., 60 min I + 180 min R). In in vitro tests (enzyme activity and SRBC lysis) C1s-INH-248 demonstrated profound inhibitory potency. In vivo C1s-INH-248 (1 mg/kg body weight) administered 5 min before reperfusion significantly attenuated myocardial injury (31.9 +/- 2.5 vs 8.9 +/- 1.6% necrosis/area at risk; p < 0.01). The cardioprotective effect was dose dependent. The reduction of myocardial injury was also observed as diminished plasma creatine kinase activity in C1s-INH-248-treated animals (70.7 +/- 6.8 vs 45.1 +/- 3.9 U/g protein after 3 h of reperfusion,p < 0.05). Further, cardiac myeloperoxidase activity (i.e., a marker of PMN accumulation) in the ischemic and necrotic area was significantly reduced following C1s-INH-248 treatment (1.31 +/- 0.23 vs 0.4 +/- 0.05 U/100 mg tissue in necrotic area, p < 0.01). Thus, blocking the classical complement pathway with a highly specific and potent synthetic inhibitor of the activated C1 complex appears to bean effective mean to preserve Ischemic myocardium from injury following reperfusion.
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收藏
页码:5375 / 5380
页数:6
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