Induction of heat shock proteins by tyrosine kinase inhibitors in rat cardiomyocytes and myogenic cells confers protection against simulated ischemia.
Previous studies have shown that in rodent myogenic cells and in the hearts of transgenic mice in which heat shock protein expression is increased there is a marked tolerance to ischemic/reperfusion injury. Furthermore, a recent study has shown that the benzoquinoid ansamycin antibiotic and tyrosine kinase inhibitor, herbimycin A, is capable of inducing the expression of heat shock proteins in fibroblasts. Our intention, in the present study, was to investigate if exposure of rat cardiomyocytes 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 antibiotic, geldanamycin. We found that cells exposed to these compounds overexpressed heat shock proteins and are also rendered more tolerant to 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 benzoquinoid ansamycin antibiotics, or closely related analogues, may offer a pharmacological means of increasing the level of heat shock proteins in cardiac tissue and thus protect the heart against ischemic/reperfusion injury.
Conde
A G
AG
Department of Medicine, Division of Endocrinology & Metabolism, University of California, San Diego, La Jolla, CA 92093-0618, USA.
Lau
S S
SS
Dillmann
W H
WH
Mestril
R
R
D000818:Animals; D000831:Animals, Newborn; D016227:Benzoquinones; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000096:biosynthesis*; D006358:Hot Temperature; D047029:Lactams, Macrocyclic; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011809:Quinones / Q000494:pharmacology*; D051381:Rats; D017828:Rifabutin / Q000031:analogs & derivatives; D019311:Staurosporine / Q000494:pharmacology; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014638:Vanadates / Q000494:pharmacology
D016227:Benzoquinones; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011809:Quinones; D014157:Transcription Factors; D017828:Rifabutin; D014638:Vanadates; C020754:herbimycin; D011505:Protein-Tyrosine Kinases; D019311:Staurosporine; C001277:geldanamycin