title: Role of heat shock factor-1 activation in the doxorubicin-induced heart failure in mice.
abstract: Treating cancer patients with chemotherapeutics, such as doxorubicin (Dox), cause dilated cardiomyopathy and congestive heart failure because of 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. 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 twofold 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 coimmunoprecipitate 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 showed significantly reduced Dox-induced heart failure and higher survival rate, and there was no change in Bax upon treating with Dox in HSF-1(-/-) mice. From these results we propose a novel mechanism for Dox-induced heart failure: increased expression of Hsp25 because of oxidant-induced activation of HSF-1 transactivates p53 to increase Bax levels, which leads to heart failure.
authors.affiliation: Division of Cardiovascular medicine, Davis Heart & Lung Research Institute, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: Kaushik
authors.initials: K
authors.lastname: Vedam
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Nishijima
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Druhan
authors.forename: Mahmood
authors.initials: M
authors.lastname: Khan
authors.forename: Nicanor I
authors.initials: NI
authors.lastname: Moldovan
authors.forename: Jay L
authors.initials: JL
authors.lastname: Zweier
authors.forename: Govindasamy
authors.initials: G
authors.lastname: Ilangovan
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000009:adverse effects*; D006333:Heart Failure / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology*; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; C486113:Hsbp1 protein, mouse; C490017:Hsf1 protein, mouse; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D004317:Doxorubicin