Specific induction of the 70-kD heat stress proteins by the tyrosine kinase inhibitor herbimycin-A protects rat neonatal cardiomyocytes - A new pharmacological route to stress protein expression?

被引:78
作者
Morris, SD
Cumming, DVE
Latchman, DS
Yellon, DM
机构
[1] UCL HOSP, DEPT ACAD & CLIN CARDIOL, HATTER INST CARDIOVASC STUDIES, LONDON WC1E 6DB, ENGLAND
[2] UCL, SCH MED, DEPT MOLEC PATHOL, LONDON W1P GDB, ENGLAND
基金
英国惠康基金;
关键词
myocardial protection; heat shock proteins; myocardial infarction; primary cardiomyocyte;
D O I
10.1172/JCI118468
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Heat shock protein (hsp) induction by stressful stimuli such as heat and ischemia is known to protect cardiac cells from severe stress. The ability to induce hsp's in the heart directly by ''nonstressful'' means would potentially have important clinical implications. In noncardiac cells. the tyrosine kinase inhibitor herbimycin-X has been shown to induce the 72-kD hsp. We therefore examined whether herbimycin-A and another tyrosine kinase inhibitor, genistein, could induce 70-kD hsp's in primary cultures of rat neonatal cardiomyocytes, and whether these treatments protect against severe stress. Primary cardiomyocytes were incubated with herbimycin-A or genistein. hsp induction was measured 16-20 h later by Western blotting. Cell survival after subsequent lethal heat stress or simulated ischemia was assessed using trypan blue exclusion and released lactate dehydrogenase activity. Our results indicate that, in cardiac cells, herbimycin-A induces 70-kD hsp's but not hsp90, -60, -25, or glucose-regulated protein 78, whereas genistein has no effect on hsp's. Moreover, hsp induction correlated with the ability of herbimycin-A to protect cells against severe stress, whereas genistein had no protective effects. This suggests that herbimycin-A may induce 70-kD hsp's via a tyrosine kinase-independent mechanism. These results indicate the possibility of a pharmacological approach to HSP70 induction and cardiac protection, which may ultimately be of clinical relevance.
引用
收藏
页码:706 / 712
页数:7
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