Radicicol activates heat shock protein expression and cardioprotection in neonatal rat cardiomyocytes.
Heat shock proteins (HSPs) constitute an endogenous cellular defense mechanism against environmental stresses. In the past few years, studies have shown that overexpression of HSPs can protect cardiac myocytes against ischemia-reperfusion injury. In an attempt to increase the HSPs in cardiac tissue, we used the compound radicicol that activates HSP expression by binding to the HSP 90 kDa (HSP90). HSP90 is the main component of the cytosolic molecular chaperone complex, which has been implicated in the regulation of the heat shock factor 1 (HSF1). HSF1 is responsible for the transcriptional activation of the heat shock genes. In the present study, we show that radicicol induces HSP expression in neonatal rat cardiomyocytes, and this increase in HSPs confers cardioprotection to these cardiomyocytes. We also show that radicicol induction of the HSP and cardioprotection is dependent on the inhibition of HSP90 in cardiomyocytes. These results indicate that modulation of the active HSP90 protein level plays an important role in cardioprotection. Therefore, compounds, such as radicicol and its possible derivatives that inhibit the function of HSP90 in the cell may represent potentially useful cardioprotective agents.
Griffin
Tina M
TM
Department of Physiology and the Cardiovascular Institute, Loyola University Medical Center, Maywood, Illinios 60153, USA.
Valdez
Tina V
TV
Mestril
Ruben
R
D000818:Animals; D000831:Animals, Newborn; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D018942:Macrolides; D017202:Myocardial Ischemia / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors
D002316:Cardiotonic Agents; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D018841:HSP90 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; C000619709:Hsf1 protein, rat; D007783:Lactones; D018942:Macrolides; D014157:Transcription Factors; C035359:monorden