Karthikeyan Krishnamurthy1, Shannon Glaser2, Gianfranco D Alpini2, Arturo J Cardounel3, Zhenguo Liu1, Govindasamy Ilangovan4. 1. Division of Cardiovascular Medicine, Department of Internal Medicine, Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA. 2. 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. 3. Department of Anesthesiology, The Ohio State University, Columbus, OH 43210, USA. 4. 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.
Abstract
AIMS: 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. METHODS AND RESULTS: 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. CONCLUSION: 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. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: 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. METHODS AND RESULTS: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. CONCLUSION: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. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Eileen M Burkart; Nandakumar Sambandam; Xianlin Han; Richard W Gross; Michael Courtois; Carolyn M Gierasch; Kooresh Shoghi; Michael J Welch; Daniel P Kelly Journal: J Clin Invest Date: 2007-12 Impact factor: 14.808
Authors: Marie-Christine Gerbod-Giannone; Yankun Li; Adriaan Holleboom; Seongah Han; Li-Chung Hsu; Ira Tabas; Alan R Tall Journal: Proc Natl Acad Sci U S A Date: 2006-02-21 Impact factor: 11.205