title: Ursodeoxycholic Acid (UDCA) Exerts Anti-Atherogenic Effects by Inhibiting RAGE Signaling in Diabetic Atherosclerosis.
abstract: A naturally occurring bile acid, ursodeoxycholic acid (UDCA), is known to alleviate endoplasmic reticulum (ER) stress at the cellular level. However, the detailed action mechanisms of UDCA in atherosclerosis are not fully understood. In this study, we demonstrated whether UDCA exerts anti-atherogenic activity in diabetic atherosclerosis by targeting ER stress and "receptor for advanced glycation endproduct" (RAGE) signaling. UDCA markedly reduced ER stress, RAGE expression, and pro-inflammatory responses [including NF-κB activation and reactive oxygen species (ROS) production] induced in endothelial cells (ECs) by high glucose (HG). In particular, UDCA inhibited HG-induced ROS production by increasing the Nrf2 level. In macrophages, UDCA also blocked HG-induced RAGE and pro-inflammatory cytokine expression and inhibited foam cell formation via upregulation of the ATP-binding cassette (ABC) transporters, ABCA1 and ABCG1. In the diabetic mouse model, UDCA inhibited atheromatous plaque formation by decreasing ER stress, and the levels of RAGE and adhesion molecules. In conclusion, UDCA exerts an anti-atherogenic activity in diabetic atherosclerosis by targeting both ER stress and RAGE signaling. Our work implicates UDCA as a potential therapeutic agent for prevention or treatment of diabetic atherosclerosis.
authors.affiliation: Medical Research Institute, School of Medicine, Ewha Womans University, Seoul, Korea.
authors.forename: Jihwa
authors.initials: J
authors.lastname: Chung
authors.affiliation: Medical Research Institute, School of Medicine, Ewha Womans University, Seoul, Korea.
authors.forename: Shung Hyun
authors.initials: SH
authors.lastname: An
authors.affiliation: Center for Cell Signaling Research and Division of Molecular Life Sciences, Ewha Womans University, Seoul, Korea.
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Kang
authors.affiliation: Medical Research Institute, School of Medicine, Ewha Womans University, Seoul, Korea.|Department of Internal Medicine, Cardiology Division and GT5 Program of Ewha Womans University School of Medicine, Seoul, Korea.
authors.forename: Kihwan
authors.initials: K
authors.lastname: Kwon
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003925:Diabetic Angiopathies / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D058226:Plaque, Atherosclerotic / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*
chemical_list: D016328:NF-kappa B; D017382:Reactive Oxygen Species; D000067759:Receptor for Advanced Glycation End Products; D014580:Ursodeoxycholic Acid