热休克蛋白72在心肌缺血再灌注损伤期间增强锰超氧化物歧化酶活性，与线粒体保护和细胞凋亡减少相关。

Heat shock protein 72 enhances manganese superoxide dismutase activity during myocardial ischemia-reperfusion injury, associated with mitochondrial protection and apoptosis reduction.

作者信息

Suzuki Ken, Murtuza Bari, Sammut Ivan A, Latif Najma, Jayakumar Jay, Smolenski Ryszard T, Kaneda Yasufumi, Sawa Yoshiki, Matsuda Hikaru, Yacoub Magdi H

机构信息

Harefield Heart Science Centre, Imperial College Faculty of Medicine, Middlesex, UK.

出版信息

Circulation. 2002 Sep 24;106(12 Suppl 1):I270-6.

PMID:12354745

Abstract

BACKGROUND

Heat shock protein 72 (HSP72) is known to provide myocardial protection against ischemia-reperfusion injury by its chaperoning function. Target molecules of this effect are presumed to include not only structural proteins but also other self-preservation proteins. The details, however, remain unknown. Manganese superoxide dismutase (Mn-SOD) is an enzyme that preserves mitochondria, a key organelle for cellular respiration, from reperfusion injury and limits mitochondria-related apoptosis. We hypothesized that Mn-SOD would play a role in HSP72-mediated cardioprotection.

METHODS AND RESULTS

Rat hearts were transfected with human HSP72 by intra-coronary infusion of Hemagglutinating Virus of Japan-liposome, resulting in global myocardial overexpression of HSP72. After ischemia-reperfusion injury, cardiac function (left ventricular systolic pressure, maximum dP/dt, minimum dP/dt, and coronary flow) was improved in the HSP72-transfected hearts compared with control-transfected ones, corresponding with less leakage of creatine kinase and mitochondrial aspartate aminotransferase. Postischemic Mn-SOD content and activity in the HSP72-transfected hearts were enhanced in comparison with the controls (content: 96.9+/-4.1 versus 85.5+/-2.5% to the preischemic level, P=0.038; activity: 93.9+/-2.2 versus 82.2+/-3.7%, P=0.022), associated with improved mitochondrial respiratory function (postischemic percent respiratory control index; NAD(+)-linked: 81.3+/-3.8 versus 18.5+/-4.4%; FAD-linked: 71.8+/-5.5 versus 20.7+/-5.3%, P<0.001). In addition, incidence of postischemic cardiomyocyte apoptosis was attenuated in the HSP72-transfected hearts (4.0+/-1.1 versus 10.3+/-3.3%, P=0.036), correlating with an increased Bcl-2 level and reduced up-regulation of caspase-3.

CONCLUSIONS

These data suggest that the enhanced Mn-SOD activity during ischemia-reperfusion injury, which is associated with mitochondrial protection and apoptosis reduction, is a possible mechanism of HSP72-induced cardioprotection.

摘要

背景

热休克蛋白72（HSP72）通过其伴侣功能为心肌提供抗缺血再灌注损伤的保护作用。这种效应的靶分子推测不仅包括结构蛋白，还包括其他自我保护蛋白。然而，具体细节仍不清楚。锰超氧化物歧化酶（Mn-SOD）是一种保护线粒体（细胞呼吸的关键细胞器）免受再灌注损伤并限制线粒体相关凋亡的酶。我们假设Mn-SOD在HSP72介导的心脏保护中发挥作用。

方法与结果

通过冠状动脉内输注日本血凝病毒-脂质体将人HSP72转染到大鼠心脏，导致HSP72在全心肌中过表达。缺血再灌注损伤后，与对照转染的心脏相比，HSP72转染的心脏的心功能（左心室收缩压、最大dP/dt、最小dP/dt和冠状动脉血流量）得到改善，同时肌酸激酶和线粒体天冬氨酸转氨酶的漏出减少。与对照组相比，HSP72转染的心脏缺血后Mn-SOD含量和活性增强（含量：相对于缺血前水平为96.9±4.1%对85.5±2.5%，P=0.038；活性：93.9±2.2%对82.2±3.7%，P=0.022），这与线粒体呼吸功能改善相关（缺血后呼吸控制指数百分比；NAD(+)连接：81.3±3.8%对18.5±4.4%；FAD连接：71.8±5.5%对20.7±5.3%，P<0.001）。此外，HSP72转染的心脏缺血后心肌细胞凋亡发生率降低（4.0±1.1%对10.3±3.3%，P=0.036），这与Bcl-2水平升高和caspase-3上调减少相关。