title: Hsp70 regulates the doxorubicin-mediated heart failure in Hsp70-transgenic mice.
abstract: The aim of this study was to investigate the potential protective effect of the Hsp70 protein in the cardiac dysfunction induced by doxorubicin (DOX) and the mechanisms of its action. For this purpose, we used both wild-type mice (F1/F1) and Hsp70-transgenic mice (Tg/Tg) overexpressing human HSP70. Both types were subjected to chronic DOX administration (3 mg/kg intraperitoneally every week for 10 weeks, with an interval from weeks 4 to 6). Primary cell cultures isolated from embryos of these mice were also studied. During DOX administration, the mortality rate as well as weight reduction were lower in Tg/Tg compared to F1/F1 mice (P < 0.05). In vivo cardiac function assessment by transthoracic echocardiography showed that the reduction in left ventricular systolic function observed after DOX administration was lower in Tg/Tg mice (P < 0.05). The study in primary embryonic cell lines showed that the apoptosis after incubation with DOX was reduced in cells overexpressing Hsp70 (Tg/Tg), while the apoptotic pathway that was activated by DOX administration involved activated protein factors such as p53, Bax, caspase-9, caspase-3, and PARP-1. In myocardial protein extracts from identical mice with DOX-induced heart failure, the particular activated apoptotic pathway was confirmed, while the presence of Hsp70 appeared to inhibit the apoptotic pathway upstream of the p53 activation. Our results, in this DOX-induced heart failure model, indicate that Hsp70 overexpression in Tg/Tg transgenic mice provides protection from myocardial damage via an Hsp70-block in p53 activation, thus reducing the subsequent apoptotic mechanism.
authors.affiliation: Department of Cardiology and Michaelidion Cardiac Center, Medical School, University of Ioannina, Ioannina, 45110, Greece, anaka@cc.uoi.gr.
authors.forename: Katerina
authors.initials: K
authors.lastname: Naka K
authors.forename: Patra
authors.initials: P
authors.lastname: Vezyraki
authors.forename: Alexandros
authors.initials: A
authors.lastname: Kalaitzakis
authors.forename: Stelios
authors.initials: S
authors.lastname: Zerikiotis
authors.forename: Lampros
authors.initials: L
authors.lastname: Michalis
authors.forename: Charalampos
authors.initials: C
authors.lastname: Angelidis
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D004195:Disease Models, Animal; D004317:Doxorubicin; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006333:Heart Failure / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D013599:Systole; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D016277:Ventricular Function, Left
chemical_list: D018840:HSP70 Heat-Shock Proteins; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin
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