title: A brief elevation of serum amyloid A is sufficient to increase atherosclerosis.
abstract: Serum amyloid A (SAA) has a number of proatherogenic effects including induction of vascular proteoglycans. Chronically elevated SAA was recently shown to increase atherosclerosis in mice. The purpose of this study was to determine whether a brief increase in SAA similarly increased atherosclerosis in a murine model. The recombination activating gene 1-deficient (rag1(-/-)) × apolipoprotein E-deficient (apoe(-/-)) and apoe(-/-) male mice were injected, multiple times or just once respectively, with an adenoviral vector encoding human SAA1 (ad-SAA); the injected mice and controls were maintained on chow for 12-16 weeks. Mice receiving multiple injections of ad-SAA, in which SAA elevation was sustained, had increased atherosclerosis compared with controls. Strikingly, mice receiving only a single injection of ad-SAA, in which SAA was only briefly elevated, also had increased atherosclerosis compared with controls. Using in vitro studies, we demonstrate that SAA treatment leads to increased LDL retention, and that prevention of transforming growth factor beta (TGF-β) signaling prevents SAA-induced increases in LDL retention and SAA-induced increases in vascular biglycan content. We propose that SAA increases atherosclerosis development via induction of TGF-β, increased vascular biglycan content, and increased LDL retention. These data suggest that even short-term inflammation with concomitant increase in SAA may increase the risk of developing CVD.
authors.affiliation: Department of Internal Medicine, Division of Endocrinology and Molecular Medicine, University of Kentucky, Lexington, KY Department of Pharmacology and Nutritional Sciences, Division of Nutritional Sciences, University of Kentucky, Lexington, KY.
authors.forename: Joel C
authors.initials: JC
authors.lastname: Thompson
authors.affiliation: Department of Internal Medicine, Division of Endocrinology and Molecular Medicine, University of Kentucky, Lexington, KY.
authors.forename: Colton
authors.initials: C
authors.lastname: Jayne
authors.affiliation: Department of Internal Medicine, Division of Endocrinology and Molecular Medicine, University of Kentucky, Lexington, KY.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Thompson
authors.affiliation: Department of Internal Medicine, Division of Endocrinology and Molecular Medicine, University of Kentucky, Lexington, KY.
authors.forename: Patricia G
authors.initials: PG
authors.lastname: Wilson
authors.affiliation: Department of Internal Medicine, Division of Endocrinology and Molecular Medicine, University of Kentucky, Lexington, KY.
authors.forename: Meghan H
authors.initials: MH
authors.lastname: Yoder
authors.affiliation: Department of Pharmacology and Nutritional Sciences, Division of Nutritional Sciences, University of Kentucky, Lexington, KY Barnstable Brown Diabetes and Obesity Research Center, University of Kentucky, Lexington, KY.
authors.forename: Nancy
authors.initials: N
authors.lastname: Webb
authors.affiliation: Department of Internal Medicine, Division of Endocrinology and Molecular Medicine, University of Kentucky, Lexington, KY Barnstable Brown Diabetes and Obesity Research Center, University of Kentucky, Lexington, KY Department of Veterans Affairs, Lexington, KY.
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Tannock
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011509:Proteoglycans / Q000378:metabolism; D000685:Serum Amyloid A Protein / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta
chemical_list: D001057:Apolipoproteins E; D018398:Homeodomain Proteins; D011509:Proteoglycans; D000685:Serum Amyloid A Protein; D016212:Transforming Growth Factor beta; C064658:RAG-1 protein
keywords: apolipoproteins; cardiovascular disease; extracellular matrix; free-form: biglycan; lipoproteins; proteoglycans; transforming growth factor beta; vascular biology