Heat Shock Factor‐1 Knock Out Protects From Doxorubicin‐Induced Heart Failure

Abstract

Doxorubicin (DOX) induces oxidative stress in the heart and congestive heart failure (CHF) among cohort of cancer patients, who are treated with this drug for various malignancies. On the other hand, heat shock factor 1 (HSF‐1) is activated by heat stress and various oxidants. Thus we hypothesized that activation of HSF‐1 by the DOX‐generated oxidants may play a role in the occurrence of CHF and hence knocking HSF‐1 out might protect the heart from DOX. Wild type (HSF‐1+/+) and HSF‐1 knock out (HSF‐1−/−) mice (n=10 in each group) were injected (IP) with DOX at a dose of 6mg/kg for 4 weeks. At the 8th week, CHF was confirmed from the reduced ejection fraction, by echocardiography. There was a significant delay in occurrence of CHF in HSF‐1−/− mice compared to HSF‐1+/+group. In DOX treated HSF‐1+/+ hearts, more than three fold increase in the expression of Hsp25 and phospho (s‐15 & s‐82) Hsp25 (2D western blotting & Ms/Ms analysis), was observed. Further, immunoprecipitation (ip) experiments showed that p53 co‐ip Hsp25 in DOX treated hearts. Consistently, we observed higher Bax (transcripted by p53) in DOX treated HSF‐1+/+ group. However neither increased Hsp25 nor co‐ip of Hsp25 with p53 was observed in HSF‐1−/− group. We conclude from these studies that Hsp25 expression is increased in DOX treated hearts due to oxidative stress, which in turn enhances the p53 dependent pro‐apoptotic proteins such as Bax, resulting in CHF.