Abstract 1053: The Role Of Bile Acid-initiated Signaling In Vascular Smooth Muscle Cell Phenotypic Switching And Atherosclerosis

Atherosclerosis is a chronic inflammatory disease in which foam cells (lipid-laden macrophage-like cells) accumulate in the arterial wall. Vascular smooth muscle cells (VSMCs) are not terminally differentiated; they switch to a foam cell-like phenotype in response to various stimuli, such as cholesterol (CHOL), increasing susceptibility to vascular diseases. Modulated SMCs are the main contributors to atherosclerotic plaque formation. The intracellular metabolism of CHOL via peroxisomes in hepatocytes produces bile acids like cholic or deoxycholic acid, which agonize liver X receptor (LXR). LXR facilitates the first step of reverse CHOL transport. It is unknown if VSMCs synthesize bile acids and whether peroxisomes and the bile acids they produce play a role in VSMC-derived foam cell formation. Using human aortic SMCs (HASMCs), we found that CHOL treatment decreased expression of several peroxisomal proteins. Peroxisomal loss-of-function experiments demonstrated increased intracellular lipid accumulation, as visualized with Oil Red O (ORO) staining. We have shown that HASMCs synthesize bile acids after exposure to CHOL, which led us to hypothesize that bile acid-initiated signaling participates in the phenotypic modulation initiated by CHOL in VSMCs. Treatment of HASMCs with LXR agonists or bile acids increased expression of the efflux CHOL transporter ABCA1, bile acid-related peroxisomal enzymes, and differentiation markers; they decreased expression of macrophage and foam cell markers and ORO staining. These data show that VSMCs have the metabolic capacity to synthesize bile acids, which is impaired if peroxisomes are non-functional or absent. Our data indicates that activation of bile acid receptors upregulates ABCA1, favoring a differentiated VSMC phenotype. Together, these data suggest that activation of LXR plays a role in CHOL-induced VSMC to foam cell transition and that LXR is a potential therapeutic target which promotes VSMC differentiation and decreases atherosclerotic plaque formation.