title: Heat shock transcription factor 1 protects heart after pressure overload through promoting myocardial angiogenesis in male mice.
abstract: Heat shock transcription factor 1 (HSF1) plays an important role not only in excise-induced cardiac hypertrophy but also in protection against pressure overload-induced cardiac dysfunction. However, the mechanism is not completely understood. We here elucidate the potential mechanisms by which HSF1 protects against pressure overload-induced cardiac remodeling and dysfunction. A sustained constriction of transverse aorta (TAC) was imposed to HSF1 transgenic (TG), knockout (KO) and their littermate wild type (WT) male mice. Four weeks later, adaptive responses to TAC, such as cardiac hypertrophy, contractility and angiogenesis evaluated by echocardiography, catheterization, coronary perfusion pressure and immunohistochemistry were well preserved in TG but not in KO compared with WT mice. An angiogenesis inhibitor TNP-470 abrogated all these adaptive responses in TG mice, while cardiac transfection of VEGF with angiopoietin-1 rescued the broken heart in KO mice. In response to TAC, p53 was downregulated and hypoxia-inducing transcription factor-1 (HIF-1) was upregulated not only in the heart but also in the cultured cardiac endothelial cells (EC) of TG mice as compared to WT mice whereas these changes became opposite in KO mice. A small interfering RNA (siRNA) of HIF-1 but not a p53 gene impaired the adaptive responses of the heart and EC in TG mice, and a siRNA of p53 but not a HIF-1 gene significantly reversed the heart and EC disorders in KO mice after TAC. We conclude that HSF1 promotes cardiac angiogenesis through suppression of p53 and subsequent upregulation of HIF-1 in endothelial cells during chronic pressure overload, leading to the maintenance of cardiac adaptation.
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China. zou.yunzeng@zs-hospital.sh.cn
authors.forename: Yunzeng
authors.initials: Y
authors.lastname: Zou
authors.forename: Jiming
authors.initials: J
authors.lastname: Li
authors.forename: Hong
authors.initials: H
authors.lastname: Ma
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.forename: Jie
authors.initials: J
authors.lastname: Yuan
authors.forename: Hui
authors.initials: H
authors.lastname: Gong
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Liang
authors.forename: Aili
authors.initials: A
authors.lastname: Guan
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Ning
authors.initials: N
authors.lastname: Zhou
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Niu
authors.forename: Aijun
authors.initials: A
authors.lastname: Sun
authors.forename: Akira
authors.initials: A
authors.lastname: Nakai
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takano
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
authors.forename: Junbo
authors.initials: J
authors.lastname: Ge
mesh_terms: D020533:Angiogenesis Inhibitors / Q000009:adverse effects; D042683:Angiopoietin-1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D003250:Constriction; D003510:Cyclohexanes / Q000009:adverse effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004452:Echocardiography; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020868:Gene Silencing / Q000187:drug effects; D000076249:Heat Shock Transcription Factors; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics*; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D011312:Pressure / Q000009:adverse effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D012717:Sesquiterpenes / Q000009:adverse effects; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology
chemical_list: D020533:Angiogenesis Inhibitors; D042683:Angiopoietin-1; D003510:Cyclohexanes; D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; D034741:RNA, Small Interfering; D012717:Sesquiterpenes; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D000077609:O-(Chloroacetylcarbamoyl)fumagillol