herbimycin and Myocardial-Ischemia

The heat shock proteins (hsps) are induced by a variety of stressful stimuli and their overexpression has been shown to protect cells both in vitro and in vivo against such stimuli, as well as against stimuli-inducing apoptosis. The potential therapeutic benefit of elevating hsp levels in individuals with, for example, cerebral or cardiac ischaemia or neurodegenerative diseases has led to the identification of specific methods of inducing hsp expression in a non-stressful manner. These include pharmacological procedures and cytokine treatment to elevate endogenous hsp levels and the development of viral vectors to deliver exogenous hsp genes. The advantages and disadvantages of each of these methods and their ultimate therapeutic potential are discussed.

Topics: Apoptosis; Benzoquinones; Brain Ischemia; Cytokines; Cytoprotection; Genetic Therapy; Heat-Shock Proteins; Humans; Imides; Lactams, Macrocyclic; Myocardial Ischemia; Neurodegenerative Diseases; Pyridines; Rifabutin

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-A 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 has 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.

Topics: Animals; Benzoquinones; Cell Death; Cell Survival; Cells, Cultured; Enzyme Inhibitors; Genistein; Heart; Heat-Shock Response; HSP70 Heat-Shock Proteins; Isoflavones; Lactams, Macrocyclic; Myocardial Ischemia; Myocardium; Protein-Tyrosine Kinases; Quinones; Rats; Rats, Sprague-Dawley; Rifabutin