INDUCTION OF HEAT-SHOCK PROTEINS BY TYROSINE KINASE INHIBITORS IN RATCARDIOMYOCYTES AND MYOGENIC CELLS CONFERS PROTECTION AGAINST SIMULATED ISCHEMIA

Previous studies have shown that in rodent myogenic cells and in the h earts of transgenic mice in which heat shock protein expression is inc reased there is a marked tolerance to ischemic/reperfusion injury. fur thermore, a recent study has shown that the benzoquinoid ansamycin ant ibiotic and tyrosine kinase inhibitor, herbimycin A, is capable of ind ucing the expression of heat shock proteins in fibroblasts, Our intent ion, in the present study, was to investigate if exposure of rat cardi omyocytes and the myogenic cell line H9c2 to herbimycin A would induce these proteins and, thus, confer protection against ischemic stress. For this purpose, we exposed both rat neonatal cardiomyocytes and H9c2 cells to herbimycin A and another related benzoquinoid ansamycin anti biotic, geldanamycin. We found that cells exposed to these compounds o verexpressed heat shock proteins and are also rendered more tolerant t o simulated ischemia as measured by the release of cytoplasmic enzymes . In addition, we found that the mechanism of induction of heat shock proteins by these compounds is similar, if not identical, to that of a heat shock (42 degrees C, 60 min). These results suggest that these b enzoquinoid ansamycin antibiotics, or closely related analogues, may o ffer a pharmacological means of increasing the level of heat shock pro teins in cardiac tissue and thus protect the heart against, ischemic/r eperfusion injury. (C) 1997 Academic Press Limited.