Matrix metalloproteinase-2 contributes to ischemia-reperfusion injury in the heart
Matrix metalloproteinase-2 contributes to ischemia-reperfusion injury in the heart
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DOI：
10.1161/01.cir.101.15.1833
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发表时间：
2000-04-18
期刊：
影响因子：
37.8
通讯作者：
Schulz, R
中科院分区：
文献类型：
--
作者：
Cheung, PY;Sawicki, G;Schulz, R
背景-基质金属蛋白酶（MMP）有助于心肌梗塞后胶原蛋白的降解和细胞外基质的重塑；然而，它们在缺血和再灌注后心肌功能障碍中的作用尚不清楚。方法和结果-我们测量了缺血后有氧灌注和再灌注过程中MMP 释放到离体、灌注大鼠心脏的冠状流出物中的情况。有氧灌注对照心脏表达 pro-MMP-2 和 MMP-2，以及一种未鉴定的 75-kDa 明胶酶。在冠状动脉流出物中也检测到这些酶，在全无血流缺血20分钟后，冠状动脉流出物中pro-MMP-2显着增加，并在再灌注第一分钟内达到峰值。再灌注期间pro-MMP-2释放到冠状流出物中随着缺血持续时间的增加而增强，并且与再灌注期间机械功能的恢复呈负相关(r(2)=0.99)。 MMP-2抗体(1.5至15μg/mL)以及MMPs多西环素(10至100μmol/L)和邻菲咯啉(3至100μmol/L)抑制剂改善了再灌注期间机械功能的恢复，而MMP-2使再灌注期间机械功能的恢复恶化。结论-这些结果表明，缺血后再灌注期间MMP-2的急性释放导致心脏机械功能障碍。抑制MMPs可能是治疗缺血再灌注损伤的一种新的药理学策略。
Background-Matrix metalloproteinases (MMPs) contribute to collagen degradation and remodeling of the extracellular matrix after myocardial infarction; however, their role in myocardial dysfunction immediately after ischemia and reperfusion is unknown.Methods and Results-We measured the release of MMPs into the coronary effluent of isolated, perfused rat hearts during aerobic perfusion and reperfusion after ischemia. Aerobically perfused control hearts expressed pro-MMP-2 and MMP-2, as well as an unidentified 75-kDa gelatinase. These enzymes were also detected in the coronary effluent, After 20 minutes of global no-flow ischemia, there was a marked increase in pro-MMP-2 in the coronary effluent that peaked within the first minute of reperfusion, The release of pro-MMP-2 into the coronary effluent during reperfusion was enhanced with increasing duration of ischemia and correlated negatively with the recovery of mechanical function during reperfusion (r(2)=0.99). MMP-2 antibody (1.5 to 15 mu g/mL) and the inhibitors of MMPs doxycycline (10 to 100 mu mol/L) and o-phenanthroline (3 to 100 mu mol/L) improved whereas MMP-2 worsened the recovery of mechanical function during reperfusion,Conclusions-These results show that acute release of MMP-2 during reperfusion after ischemia contributes to cardiac mechanical dysfunction. The inhibition of MMPs may be a novel pharmacological strategy for the treatment of ischemia-reperfusion injury.