Abstract 285: SAA, but not CRP, Stimulates Vascular Proteoglycan Synthesis in a Pro-Atherogenic Manner
Inflammation is a hallmark of atherosclerosis. Inflammatory markers such as C reactive protein (CRP) and serum amyloid A (SAA) are predictive of cardiovascular disease in clinical trials. It is controversial as to whether CRP and SAA are actually risk factors influencing the development of atherosclerosis, or merely reflect the burden of disease. Proteoglycan mediated lipoprotein retention is one of the earliest steps in the initiation of atherosclerosis. We tested the hypothesis that CRP and/or SAA could directly influence atherogenesis via increasing vascular proteoglycan synthesis and lipoprotein retention. Vascular smooth muscle cells were stimulated with CRP or SAA (1–100mg/L) for 24 hours. Secreted proteoglycans were isolated, purified and characterized, and LDL binding affinity was determined by gel mobility shift assay. SAA, but not CRP, increased sulfate incorporation by up to 2.5-fold in a dose dependent manner (p<0.001). Proteoglycans synthesized by cells stimulated with SAA had increased LDL binding affinity compared to proteoglycans synthesized by unstimulated cells or cells stimulated with CRP. The increase in LDL binding affinity was due to SAA-induced elongation of glycosaminoglycan chains. Mechanistic studies indicate that SAA stimulation of proteoglycan synthesis was mediated via formyl peptide receptor like 1 (FPRL1), and was inhibited by inhibition of FPRL1 signaling. In conclusion, SAA, but not CRP, can alter vascular proteoglycan synthesis in a pro-atherogenic manner. Thus high SAA levels may actually stimulate the development of atherosclerosis, rather than merely reflecting the burden of disease.