Fan Guo-Chang, Ren Xiaoping, Qian Jiang, Yuan Qunying, Nicolaou Persoulla, Wang Yang, Jones W Keith, Chu Guoxiang, Kranias Evangelia G
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0575, USA.
Circulation. 2005 Apr 12;111(14):1792-9. doi: 10.1161/01.CIR.0000160851.41872.C6. Epub 2005 Apr 4.
Heat-shock proteins (Hsps) have been shown to render cardioprotection from stress-induced injury; however, little is known about the role of another small heat-shock protein, Hsp20, which regulates activities of vasodilation and platelet aggregation, in cardioprotection against ischemia injury. We recently reported that increased expression of Hsp20 in cardiomyocytes was associated with improved contraction and protection against beta-agonist-induced apoptosis.
To investigate whether overexpression of Hsp20 exerts protective effects in both ex vivo and in vivo ischemia/reperfusion (I/R) injury, we generated a transgenic (TG) mouse model with cardiac-specific overexpression of Hsp20 (10-fold). TG and wild-type (WT) hearts were then subjected to global no-flow I/R (45 minutes/120 minutes) using the Langendorff preparation. TG hearts exhibited improved recovery of contractile performance over the whole reperfusion period. This improvement was accompanied by a 2-fold decrease in lactate dehydrogenase released from the TG hearts. The extent of infarction and apoptotic cell death was also significantly decreased, which was associated with increased protein ratio of Bcl-2/Bax and reduced caspase-3 activity in TG hearts. Furthermore, in vivo experiments of 30-minute myocardial ischemia, via coronary artery occlusion, followed by 24-hour reperfusion, showed that the infarct region-to-risk region ratio was 8.1+/-1.1% in TG hearts (n=7), compared with 19.5+/-2.1% in WT hearts (n=11, P<0.001).
Our data demonstrate that increased Hsp20 expression in the heart protects against I/R injury, resulting in improved recovery of cardiac function and reduced infarction. Thus, Hsp20 may constitute a new therapeutic target for ischemic heart diseases.
热休克蛋白（Hsps）已被证明可对应激诱导的损伤起到心脏保护作用；然而，另一种小热休克蛋白Hsp20在抗缺血损伤的心脏保护作用方面的作用却鲜为人知，Hsp20可调节血管舒张和血小板聚集的活性。我们最近报道，心肌细胞中Hsp20表达增加与收缩功能改善及抵抗β-激动剂诱导的细胞凋亡有关。
为了研究Hsp20过表达是否在离体和体内缺血/再灌注（I/R）损伤中发挥保护作用，我们构建了心脏特异性过表达Hsp20（10倍）的转基因（TG）小鼠模型。然后使用Langendorff装置对TG和野生型（WT）心脏进行全心无血流I/R（45分钟/120分钟）。TG心脏在整个再灌注期表现出收缩功能恢复改善。这种改善伴随着TG心脏释放的乳酸脱氢酶减少2倍。梗死范围和凋亡细胞死亡程度也显著降低，这与TG心脏中Bcl-2/Bax蛋白比例增加和caspase-3活性降低有关。此外，通过冠状动脉闭塞进行30分钟心肌缺血然后再灌注24小时的体内实验表明，TG心脏的梗死区域与危险区域之比为8.1±1.1%（n = 7），而WT心脏为19.5±2.1%（n = 11，P<0.001）。
我们的数据表明，心脏中Hsp20表达增加可保护心脏免受I/R损伤，从而改善心脏功能恢复并减少梗死。因此，Hsp20可能构成缺血性心脏病的一个新的治疗靶点。
