Novel small molecule inhibitor of C1s exerts cardioprotective effects in ischemia-reperfusion injury in rabbits
Novel small molecule inhibitor of C1s exerts cardioprotective effects in ischemia-reperfusion injury in rabbits
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DOI：
10.4049/jimmunol.167.9.5375
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发表时间：
2001-11-01
影响因子：
4.4
通讯作者：
Darius, H
中科院分区：
文献类型：
--
作者：
Buerke, M;Schwertz, H;Darius, H
心肌缺血再灌注损伤可能与补体活化、趋化因子的产生、黏附分子的表达、细胞因子和氧自由基的释放以及随后的中性粒细胞聚集有关。本研究观察了新型高选择性小分子C1S抑制剂(C1s-INH-248，Knoll)对兔心肌缺血再灌注(R，60min I+180min R)模型的心脏保护作用。在体外试验(酶活性和SRBC裂解)中，C1S-INH-248表现出很强的抑制活性。在体再灌流前5min给予C1s-INH-248(1 mg/kg体重)可显著减轻心肌损伤(31.9+/-2.5vs8.9+/-1.6%坏死/危险面积；p<；0.01)。心脏保护作用呈剂量依赖关系。C1S-INH-248组再灌注3h后血浆肌酸激酶活性(70.7+/-6.8U/g蛋白比45.1+/-3.9U/g蛋白，p<；0.05)降低，心肌损伤程度减轻。此外，C1S-INH-248治疗后，缺血和坏死区心肌髓过氧化物酶活性(PMN积聚的标志)显著降低(1.31+/-0.23vs0.4+/-0.05U/100 mg组织，p<；0.01)。因此，用一种高度特异和有效的激活的C1复合体的合成抑制剂来阻断经典的补体途径似乎是保护缺血心肌免受再灌注损伤的有效手段。
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.