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Articles in PresS, published online ahead of print March 27, 2002
Am J Physiol Cell Physiol, 10.1152/ajpcell.00051.2002
Submitted on January 31, 2002
Accepted on March 23, 2002
1 School of Kinesiology, The University of Western Ontario, London, Ontario, Canada
2 School of Dentistry, Oregon Health Sciences University, Portland, Oregon, USA
3 Faculty of Physical Education and Health, University of Toronto, Toronto, Ontario, Canada
4 Department of Pharmacology and Toxicology, The University of Western Ontario, London, Ontario, Canada
5 School of Kinesiology, The University of Western Ontario, London, Ontario, Canada; Lawson Health Research Institute, London, Ontario, Canada
* To whom correspondence should be addressed. E-mail: enoble{at}julian.uwo.ca.
Because of their demonstrated potential to enhance organ and organismal survival, the mechanisms regulating heat shock protein (Hsp) expression are of particular interest. Heat shock transcription factor 1 (HSF1) mediates Hsp induction through proximal promoter heat shock elements (HSE) on hsp genes in response to proteotoxic stimuli. Experiments involving chemical induction of the response in simple biological systems have generated the hypothesis that protein denaturation, and consequential activation of HSF1, are the result of oxidation and/or depletion of intracellular thiols. Thus, the purpose of the present investigation was to determine the role of redox signaling of HSF1 in the intact animal in response to physiological and pharmacological perturbations. Heat shock and exercise induced HSF1-HSE DNA binding in the rat myocardium (p < 0.001) in the absence of changes in GSH, the major non-protein thiol in the cell. Ischemia-reperfusion, which decreased GSH content (p < 0.05), resulted in only minor, statistically non-significant HSF1-HSE formation. This dissociation between physiological induction of HSF1 and changes in GSH was not gender dependent as males and females demonstrated a similar pattern of response. Pharmacological ablation of GSH with BSO treatment increased myocardial HSF1-HSE DNA binding in estrogen naive animals (p = 0.007). Thus, while physiological induction of HSF1-HSE DNA binding is likely regulated by mediators of protein denaturation other than cellular redox status, the proposed signaling pathway may predominate with pharmacological oxidation. While the present study does not support the hypothesis that cellular oxidation is a proximal signal common to all inducers of HSF1, exploiting this signaling system may represent a plausible and accessible strategy in the development of Hsp-based therapies.
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