Published online before print October 30, 2008

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(American Journal of Pathology. 2008;173:1902-1910.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.080201

Serum Amyloid A, but Not C-Reactive Protein, Stimulates Vascular Proteoglycan Synthesis in a Pro-Atherogenic Manner

Patricia G. Wilson^*, Joel C. Thompson^*, Nancy R. Webb^*, Frederick C. de Beer^*, Victoria L. King and Lisa R. Tannock^*

From the Divisions of Endocrinology and Molecular Medicine^* and Cardiovascular Medicine, University of Kentucky, Lexington; and the Department of Veterans Affairs, Lexington, Kentucky

Inflammatory markers serum amyloid A (SAA) and C-reactive protein (CRP) are predictive of cardiac disease and are proposed to play causal roles in the development of atherosclerosis, in which the retention of lipoproteins by vascular wall proteoglycans is critical. The purpose of this study was to determine whether SAA and/or CRP alters vascular proteoglycan synthesis and lipoprotein retention in a pro-atherogenic manner. Vascular smooth muscle cells were stimulated with either SAA or CRP (1 to 100 mg/L) and proteoglycans were then isolated and characterized. SAA, but not CRP, increased proteoglycan sulfate incorporation by 50 to 100% in a dose-dependent manner (P < 0.0001), increased glycosaminoglycan chain length, and increased low-density lipoprotein (LDL) binding affinity (K_d, 29 µg/ml LDL versus 90 µg/ml LDL for SAA versus control proteoglycans; P < 0.005). Furthermore, SAA up-regulated biglycan via the induction of endogenous transforming growth factor (TGF)-β. To determine whether SAA stimulated proteoglycan synthesis in vivo, ApoE^–/– mice were injected with an adenovirus expressing human SAA-1, a null virus, or saline. Mice that received adenovirus expressing SAA had increased TGF-β concentrations in plasma and increased aortic biglycan content compared with mice that received either null virus or saline. Thus, SAA alters vascular proteoglycans in a pro-atherogenic manner via the stimulation of TGF-β and may play a causal role in the development of atherosclerosis.