Role of Heat Shock Factor 1 in Doxorubincin-Induced Cardiotoxicity

Ohio State University, Columbus OH

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Abstract

DESCRIPTION (provided by applicant): Cancer patients, who are treated with Doxorubicin (Dox) based chemotherapeutics, develop dilated cardiomyopathy (DCM) and congestive heart failure (CHF). The cause for the development of DCM and CHF has been found to be the "oxidative stress" and subsequent loss of cardiomyocytes, due to reactive oxygen species (ROS), generated by redox cycling of Dox in the heart. However, the actual mechanism on how the ROS causes HF is not completely understood yet. In our preliminary studies we have found that heat shock factor -1 (HSF-1) is activated by the ROS and heat shock protein 25 (Hsp25) expression is increased in Dox-treated hearts. Further, increased aggregation of Hsp25 and its association with p53 was found to transactivate p53 and higher transcription of Bax, a pro-apoptotic protein. This could be a major pathway of cardiomyocyte death in Dox treated hearts. Since HSF-1 is the transcription factor for Hsp25, we hypothesize that HSF-1 knock out may protect the heart from DOX induced failure. In this proposal we will evaluate this hypothesis by using HSF-1 and Hsp25 knock out mice, as experimental animal models. The present proposal has two specific aims. In the first specific aim we will apply high resolution magnetic resonance cardiac microimaging (MRI) of mouse hearts (500MHz, 11.7 T system), to non-invasively follow the progression of HF in Dox treated wild type (BALB/b), HSF-1 knock out mice, Hsp25 knock out mice, over a period of 8-10 weeks after Dox treatment. MRI enables to repeatedly follow the cardiac function of the same group of animals, over a desired period of time. Results from this specific aim will enable to quantitatively determine whether there is any difference in the occurrence of HF (or delay) among Dox-treated WT and HSF-1 or Hsp25 knock out mice. In the second specific aim, we propose to study the effect of HSF-1 or Hsp25 knock out on the magnitude of p53/Hsp25 association and Bax expression upon treating with Dox. In this specific aim we propose to use various experimental approaches such as immunoprecipitation, survival curve analysis, histochemical analysis, application of p53 inhibitors, etc to determine whether HSF-1 or Hsp25 knock out reduces the Bax induction in Dox treated hearts. Results from this specific aim will reveal, whether Hsp25/p53 pathway is a major pathway. Overall, the results from this proposal will reveal the role of HSF-1 activation and Hsp25 induction upon Dox treatment in the heart and its relevance to the observed cardiotoxicity. PUBLIC HEALTH RELEVANCE: Cancer patients, who are treated with Doxorubicin as chemotherapeutic agent, develop serious side effects such as cardiomyopathy and congestive heart failure. This grant proposal is intended to explore whether heat shock factor 1 or Heat shock protein 25 plays any role in the observed heart failure.