Delyani J A, Murohara T, Lefer A M
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Am J Physiol. 1996 Mar;270(3 Pt 2):H881-7. doi: 10.1152/ajpheart.1996.270.3.H881.
We studied the potential cardioprotective effects of the novel recombinant serine protease inhibitor (serpin), LEX-032, which inhibits the serine proteases elastase and cathepsin G. LEX-032 is a recombinant construct of human alpha 1-antichymotrypsin in which six amino acid residues were replaced around the active center with those of human alpha 1-protease inhibitor. Cats were subjected to 90 min of left anterior descending coronary artery (LAD) occlusion and 270 min of reperfusion (MI/R). Either LEX-032 or its vehicle (i.e., phosphate-buffered saline) was administered intravenously 10 min before reperfusion. Control cats were subjected to sham MI/R. Cats treated with LEX-032 demonstrated a marked reduction in cardiac necrosis after MI/R compared with cats receiving only vehicle (10 +/- 3 vs. 31 +/- 3%, P < 0.01). In addition, relaxation of LAD rings to the endothelium-dependent dilators (e.g., acetylcholine and A23187) was greater in the LEX-032-treated group than in cats receiving vehicle (72 +/- 5 vs. 52 +/- 7%, P < 0.05, and 74 +/- 8 vs. 50 +/- 8%, P < 0.05, respectively), indicating that endothelial function was preserved by LEX-032. Moreover, LEX-032 administration resulted in a marked reduction of polymorphonuclear leukocyte (PMN) adherence to ex vivo coronary vascular endothelium compared with vehicle (33 +/- 4 vs. 86 +/- 7 PMNs/mm2, P < 0.01). These data indicate that LEX-032 is a significant cardioprotective agent exerting its protective effect by inhibition of PMN-mediated cellular injury, and this agent represents a novel means of attenuating PMN-mediated reperfusion injury.
我们研究了新型重组丝氨酸蛋白酶抑制剂（丝氨酸蛋白酶抑制剂）LEX-032的潜在心脏保护作用，它可抑制丝氨酸蛋白酶弹性蛋白酶和组织蛋白酶G。LEX-032是人类α1-抗糜蛋白酶的重组构建体，其中活性中心周围的六个氨基酸残基被人类α1-蛋白酶抑制剂的相应残基取代。对猫进行90分钟的左冠状动脉前降支（LAD）闭塞和270分钟的再灌注（MI/R）。在再灌注前10分钟静脉注射LEX-032或其载体（即磷酸盐缓冲盐水）。对照猫接受假手术MI/R。与仅接受载体的猫相比，用LEX-032治疗的猫在MI/R后心脏坏死明显减少（10±3%对31±3%，P<0.01）。此外，LEX-032治疗组的LAD环对内皮依赖性舒张剂（如乙酰胆碱和A23187）的舒张作用大于接受载体的猫（分别为72±5%对52±7%，P<0.05；74±8%对50±8%，P<0.05），表明LEX-032可保留内皮功能。此外，与载体相比，给予LEX-032可使多形核白细胞（PMN）对离体冠状动脉血管内皮的粘附显著减少（33±4对86±7个PMN/mm2，P<0.01）。这些数据表明，LEX-032是一种重要的心脏保护剂，通过抑制PMN介导的细胞损伤发挥其保护作用，并且该药物代表了一种减轻PMN介导的再灌注损伤的新方法。
