Abstract 468: Serum Amyloid A and Toll-Like Receptor 2 Activation Promote Dedifferentiation of Vascular Smooth Muscle Cells

Smooth muscle cells (SMCs) regulate vascular tone, and during chronic inflammation associated with atherosclerosis, SMCs contribute to the disease process via de-differentiation from a contractile state. We study the impact of acute phase serum amyloid A (SAA), a cardiovascular risk marker that localizes to atherosclerotic plaques, on SMC function. The goal of this study was to define a role for SAA in SMC phenotypic expression. SMC marker expression was down-regulated by SAA, consistent with de-differentiation. Myocardin, a transcriptional co-activator of SMC marker gene expression, was also down-regulated by SAA, and its overexpression rescued the SAA-mediated repression of the smooth muscle α-actin and smooth muscle 22 α (SM22) promoters. SAA-mediated down-regulation of SM22 promoter activity was also rescued by expression of the myocardin family members, myocardin related transcription factor (MRTF)-A and MRTF-B. It was reported that SAA is a ligand for the Toll-like receptor (TLR)2, which has been implicated in atherosclerosis. Interestingly, FSL-1 and Pam3CSK4, known TLR2 ligands, down-regulated SM22 promoter activity, and the effects were rescued with myocardin overexpression. Moreover, knockdown of TLR2 using siRNA rescued the de-differentiated phenotype induced by SAA. In addition, SAA failed to induce de-differentiation in SMCs isolated from TLR2-/- mice. These data suggest that TLR2 activation, whether by SAA or by TLR2 ligands, promotes SMC de-differentiation characteristic of atherosclerosis.