title: Heat shock transcription factor 1 protects against pressure overload-induced cardiac fibrosis via Smad3.
abstract: Fibrotic cardiac muscle exhibits high stiffness and low compliance which are major risk factors of heart failure. Although heat shock transcription factor 1 (HSF1) was identified as an intrinsic cardioprotective factor, the role that HSF1 plays in cardiac fibrosis remains unclear. Our study aims to investigate the role of HSF1 in pressure overload-induced cardiac fibrosis and the underlying mechanism. HSF1 phosphorylation was significantly downregulated in transverse aortic constriction (TAC)-treated mouse hearts and mechanically stretched cardiac fibroblasts (cFBs). HSF1 transgenic (TG) mice, HSF1 deficient heterozygote (KO) mice, and their wild-type littermates were subjected to sham or TAC surgery for 4 weeks. HSF1 overexpression significantly attenuated pressure overload-induced cardiac fibrosis and dysfunction. Conversely, HSF1 KO mice showed deteriorated fibrotic response and cardiac dysfunction upon TAC. Moreover, we uncovered that overexpression of HSF1 protected against fibrotic response of cFBs to pressure overload. Mechanistically, we observed that the phosphorylation and the nuclear distribution of the Smad family member 3 (Smad3) were significantly decreased in HSF1-overexpressing mouse hearts, while being greatly increased in HSF1 KO mouse hearts upon TAC, compared to the control hearts, respectively. Similar alteration of Smad3 phosphorylation and nuclear distribution were found in isolated mouse cardiac fibroblasts and mechanically stretched cFBs. Constitutively active Smad3 blocked the anti-fibrotic effect of HSF1 in cFBs. Furthermore, we found a direct binding of phosphorylated HSF1 and Smad3, which can be suppressed by mechanical stress. In conclusion, the present study demonstrated for the first time that HSF1 acts as a novel negative regulator of cardiac fibrosis by blocking Smad3 activation.
  
  
  
  HSF1 activity is decreased in fibrotic hearts. HSF1 overexpression attenuates pressure overload-induced cardiac fibrosis and dysfunction. Deficiency of HSF1 deteriorates fibrotic response and cardiac dysfunction upon TAC. HSF1 inhibits phosphorylation and nuclear distribution of Smad3 via direct binding to Smad3. Active Smad3 blocks the anti-fibrotic effect of HSF1.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhou
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biological Science, Fudan University, Shanghai, 200032, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biological Science, Fudan University, Shanghai, 200032, China.
authors.forename: Xingxu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Division of Physiology, Department of Basic Sciences, School of Medicine, Loma Linda University, 11041 Campus Street, Loma Linda, 92354, CA, USA.
authors.forename: Ben
authors.initials: B
authors.lastname: Ma
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biological Science, Fudan University, Shanghai, 200032, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biological Science, Fudan University, Shanghai, 200032, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China. dwwang@tjh.tjmu.edu.cn.
authors.forename: Dao Wen
authors.initials: DW
authors.lastname: Wang
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biological Science, Fudan University, Shanghai, 200032, China. zou.yunzeng@zs-hospital.sh.cn.
authors.forename: Yunzeng
authors.initials: Y
authors.lastname: Zou
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D005355:Fibrosis; D055786:Gene Knockout Techniques; D000076249:Heat Shock Transcription Factors / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D021381:Protein Transport; D051900:Smad3 Protein / Q000032:analysis / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; D051900:Smad3 Protein
keywords: Cardiac dysfunction; Cardiac fibrosis; Fibroblasts; Heat shock transcription factor 1; Pressure overload; Smad3