Abstract 3856: Hsp25 Aggregates Transactivate p53 and Promote Heart Failure in Doxorubicin Treated Mice
Background. Treating cancer patients with chemotherapeutics, such as Doxorubicin (Dox), cause dilated cardiomyopathy and congestive heart failure, due to oxidative stress. On the other hand, heat shock factor -1 (HSF-1), a transcription factor for heat shock proteins (Hsps), is also known to be activated in response to oxidative stress. However, the possible role of HSF-1 activation and the resultant Hsp25 in chemotherapeutic-induced heart failure has not been investigated.
Methods and Results. Using HSF-1 wild type (HSF-1+/+) and knock out (HSF-1−/−) mice, we tested the hypothesis that activation of HSF-1 plays a role in the development of Dox-induced heart failure. Higher levels of Hsp25 and its phosphorylated forms were found in the failing hearts of Dox-treated HSF-1+/+ mice. More than two fold increase in Hsp25 mRNA level was found in Dox-treated hearts. Proteomic analysis showed that there is accumulation and aggregation of Hsp25 in Dox-treated failing hearts. Additionally, Hsp25 was found to co-immunoprecipitate with p53 and vice versa. Further studies indicated that the Dox-induced higher levels of Hsp25 transactivated p53 leading to higher levels of the pro-apoptotic protein Bax, but other p53 related proteins remained unaltered. Moreover, HSF-1+/+ mice treated with pifithrin-α (a p53 inhibitor) and HSF-1−/− mice showed significantly reduced Dox-induced heart failure and higher survival rate.
Conclusions. Based on these results we propose a novel mechanism for Dox-induced heart failure: increased expression of Hsp25 due to oxidant-induced activation of HSF-1 transactivates p53 to increase Bax levels, which leads to heart failure.