title: Ursodeoxycholic Acid (UDCA) Exerts Anti-Atherogenic Effects by Inhibiting Endoplasmic Reticulum (ER) Stress Induced by Disturbed Flow.
abstract: Disturbed blood flow with low-oscillatory shear stress (OSS) is a predominant atherogenic factor leading to dysfunctional endothelial cells (ECs). Recently, it was found that disturbed flow can directly induce endoplasmic reticulum (ER) stress in ECs, thereby playing a critical role in the development and progression of atherosclerosis. Ursodeoxycholic acid (UDCA), a naturally occurring bile acid, has long been used to treat chronic cholestatic liver disease and is known to alleviate endoplasmic reticulum (ER) stress at the cellular level. However, its role in atherosclerosis remains unexplored. In this study, we demonstrated the anti-atherogenic activity of UDCA via inhibition of disturbed flow-induced ER stress in atherosclerosis. UDCA effectively reduced ER stress, resulting in a reduction in expression of X-box binding protein-1 (XBP-1) and CEBP-homologous protein (CHOP) in ECs. UDCA also inhibits the disturbed flow-induced inflammatory responses such as increases in adhesion molecules, monocyte adhesion to ECs, and apoptosis of ECs. In a mouse model of disturbed flow-induced atherosclerosis, UDCA inhibits atheromatous plaque formation through the alleviation of ER stress and a decrease in adhesion molecules. Taken together, our results revealed that UDCA exerts anti-atherogenic activity in disturbed flow-induced atherosclerosis by inhibiting ER stress and the inflammatory response. This study suggests that UDCA may be a therapeutic agent for prevention or treatment of atherosclerosis.
authors.affiliation: Medical Research Institute, School of Medicine, Ewha Womans University, Seoul 158-710, Korea.
authors.forename: Jihwa
authors.initials: J
authors.lastname: Chung
authors.affiliation: Medical Research Institute, School of Medicine, Ewha Womans University, Seoul 158-710, Korea.
authors.forename: Kyoung Hwa
authors.initials: KH
authors.lastname: Kim
authors.affiliation: Medical Research Institute, School of Medicine, Ewha Womans University, Seoul 158-710, Korea.
authors.forename: Seok Cheol
authors.initials: SC
authors.lastname: Lee
authors.affiliation: Medical Research Institute, School of Medicine, Ewha Womans University, Seoul 158-710, Korea.
authors.forename: Shung Hyun
authors.initials: SH
authors.lastname: An
authors.affiliation: Medical Research Institute, School of Medicine, Ewha Womans University, Seoul 158-710, Korea.|Department of Internal Medicine, Cardiology Division and GT5 Program of Ewha Womans University School of Medicine, Seoul 158-710, Korea.
authors.forename: Kihwan
authors.initials: K
authors.lastname: Kwon
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D001775:Blood Circulation; D017536:Carotid Artery, Common / Q000503:physiopathology; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008297:Male; D051379:Mice; D009000:Monocytes / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000517:prevention & control*; D000071701:Regulatory Factor X Transcription Factors; D013314:Stress, Mechanical; D051742:Transcription Factor CHOP / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014580:Ursodeoxycholic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D000071717:X-Box Binding Protein 1
chemical_list: D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; C497250:Ddit3 protein, mouse; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; D051742:Transcription Factor CHOP; D014580:Ursodeoxycholic Acid
keywords: atherosclerosis; disturbed flow; endoplasmic reticulum stress; endothelial cells; ursodeoxycholic acid