title: Facilitatory effects of fetuin-A on atherosclerosis.
abstract: Fetuin-A is a circulating glycoprotein that is produced by liver and adipose tissue. Fetuin-A is known to induce insulin resistance and suppress vascular calcification. There are conflicting reports that show increased or decreased serum fetuin-A levels in patients with coronary artery disease (CAD). Since the role of fetuin-A in atherosclerosis remains still controversial, we aimed to clarify it in this study.
  
  
  
  We investigated the expression of fetuin-A in atheromatous plaques in CAD patients and restenosis lesions in balloon-injured rat carotid arteries in vivo. We also assessed in vitro effects of fetuin-A on inflammatory molecules in human umbilical vein endothelial cells (HUVECs), oxidized low-density lipoprotein-induced foam cell formation in human monocyte-derived macrophages, and the migration, proliferation, and extracellular matrix expression in human aortic smooth muscle cells (HASMCs) in a serum-free culture system.
  
  
  
  Fetuin-A was abundantly expressed in cultured human monocytes, macrophages, fibroblasts, HASMCs, and human coronary artery SMCs, atheromatous plaques in human coronary arteries, and restenosis lesions in rat carotid arteries. In vitro experiments showed that fetuin-A stimulated interleukin-6, monocyte chemotactic protein-1, intercellular adhesion molecule-1, and E-selectin expression in HUVECs. Fetuin-A enhanced macrophage foam cell formation associated with scavenger receptors (CD36 and SR-A) and acyl-CoA:cholesterol acyltransferase-1 up-regulation and ATP-binding cassette transporter A1 down-regulation, and increased cell proliferation and collagen-1 and -3 expression via PI3K/AKT/c-Src/NF-κB/ERK1/2 pathways in HASMCs.
  
  
  
  Our results indicate that fetuin-A exerts the stimulatory effects on inflammatory responses in HUVECs, macrophage foam cell formation, and proliferation and collagen production in HASMCs, leading to the development of atherosclerosis.
authors.affiliation: Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors.forename: Chisato
authors.initials: C
authors.lastname: Naito
authors.affiliation: Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors.forename: Mio
authors.initials: M
authors.lastname: Hashimoto
authors.affiliation: Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors.forename: Kaho
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors.forename: Remina
authors.initials: R
authors.lastname: Shirai
authors.affiliation: Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors.forename: Yui
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Kojima
authors.affiliation: Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors.forename: Rena
authors.initials: R
authors.lastname: Watanabe
authors.affiliation: Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Sato
authors.affiliation: Division of Cardiology, Showa University Fujigaoka Hospital, Yokohama, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Iso
authors.affiliation: Department of Pathology, National Cerebral and Cardiovascular Center, Osaka, Japan.
authors.forename: Taka-Aki
authors.initials: TA
authors.lastname: Matsuyama
authors.affiliation: Division of Cardiology, Showa University Fujigaoka Hospital, Yokohama, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Department of Pathology, National Cerebral and Cardiovascular Center, Osaka, Japan.
authors.forename: Hatsue
authors.initials: H
authors.lastname: Ishibashi-Ueda
authors.affiliation: Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan. Electronic address: watanabe@toyaku.ac.jp.
authors.forename: Takuya
authors.initials: T
authors.lastname: Watanabe
mesh_terms: D041721:3T3-L1 Cells; D000328:Adult; D000818:Animals; D002339:Carotid Arteries / Q000378:metabolism* / Q000473:pathology; D020212:Carotid Artery Injuries / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003324:Coronary Artery Disease / Q000378:metabolism* / Q000473:pathology; D003331:Coronary Vessels / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000378:metabolism; D005487:Foam Cells / Q000378:metabolism; D006367:HeLa Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D018374:LLC-PK1 Cells; D008297:Male; D051379:Mice; D009000:Monocytes / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D058226:Plaque, Atherosclerotic; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013552:Swine; D013997:Time Factors; D055815:Young Adult; D060749:alpha-2-HS-Glycoprotein / Q000378:metabolism* / Q000494:pharmacology
chemical_list: C556354:AHSG protein, human; C071388:Ahsg protein, rat; D018836:Inflammation Mediators; D060749:alpha-2-HS-Glycoprotein
keywords: Atherosclerosis; Endothelial cell; Extracellular matrix; Fetuin-A; Macrophage; Restenosis; Vascular smooth muscle cell