title: Heat shock factor-1 knockout enhances cholesterol 7α-hydroxylase (CYP7A1) and multidrug transporter (MDR1) gene expressions to attenuate atherosclerosis.
abstract: Stress response, in terms of activation of stress factors, is known to cause obesity and coronary heart disease such as atherosclerosis in human. However, the underlying mechanism(s) of these pathways are not known. Here, we investigated the effect of heat shock factor-1 (HSF-1) on atherosclerosis.
  
  
  
  HSF-1 and low-density lipoprotein receptor (LDLr) double knockout (HSF-1(-/-)/LDLr(-/-)) and LDLr knockout (LDLr(-/-)) mice were fed with atherogenic western diet (WD) for 12 weeks. WD-induced weight gain and atherosclerotic lesion in aortic arch and carotid regions were reduced in HSF-1(-/-)/LDLr(-/-) mice, compared with LDLr(-/-) mice. Also, repression of PPAR-γ2 and AMPKα expression in adipose tissue, low hepatic steatosis, and lessened plasma adiponectins and lipoproteins were observed. In HSF-1(-/-)/LDLr(-/-) liver, higher cholesterol 7α-hydroxylase (CYP7A1) and multidrug transporter [MDR1/P-glycoprotein (P-gp)] gene expressions were observed, consistent with higher bile acid transport and larger hepatic bile ducts. Luciferase reporter gene assays with wild-type CYP7A1 and MDR1 promoters showed lesser luminescence than with mutant promoters (HSF-1 binding site deleted), indicating that HSF-1 binding is repressive of CYP7A1 and MDR1 gene expressions.
  
  
  
  HSF-1 ablation not only eliminates heat shock response, but it also transcriptionally up-regulates CYP7A1 and MDR1/P-gp axis in WD-diet fed HSF-1(-/-)/LDLr(-/-) mice to reduce atherosclerosis.
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Karthikeyan
authors.initials: K
authors.lastname: Krishnamurthy
authors.affiliation: Research, Central Texas Veterans Health Care System, Scott & White Digestive Disease Research Center, Medicine, Scott and White and Texas A&M Health Science Center, Temple, TX 76504, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: Glaser
authors.affiliation: Research, Central Texas Veterans Health Care System, Scott & White Digestive Disease Research Center, Medicine, Scott and White and Texas A&M Health Science Center, Temple, TX 76504, USA.
authors.forename: Gianfranco D
authors.initials: GD
authors.lastname: Alpini
authors.affiliation: Department of Anesthesiology, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Arturo J
authors.initials: AJ
authors.lastname: Cardounel
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Zhenguo
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA govindasamy.ilangovan@osumc.edu.
authors.forename: Govindasamy
authors.initials: G
authors.lastname: Ilangovan
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism*; D000273:Adipose Tissue / Q000201:enzymology; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D050197:Atherosclerosis / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D001665:Binding Sites; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D002340:Carotid Artery Diseases / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D002478:Cells, Cultured; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D066273:Diet, Western; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D000076249:Heat Shock Transcription Factors; D008099:Liver / Q000201:enzymology*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D047495:PPAR gamma / Q000378:metabolism; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D011401:Promoter Regions, Genetic; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; D047495:PPAR gamma; D011973:Receptors, LDL; D014157:Transcription Factors; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse; D055372:AMP-Activated Protein Kinases
keywords: Atherosclerosis; Glycoproteins; Heat shock factor; Heat shock proteins; Obesity