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.
Heat stress upregulates chaperone heat shock protein 70 and antioxidant manganese superoxide dismutase through reactive oxygen species (ROS), p38MAPK, and Akt