The Oxysterol 24(S),25-Epoxycholesterol Attenuates Human Smooth Muscle-Derived Foam Cell Formation Via Reduced Low-Density Lipoprotein Uptake and Enhanced Cholesterol Efflux

Background-Foam cell formation by intimal smooth muscle cells (SMCs) inhibits the elaboration of extracellular matrix, which is detrimental to plaque stabilization. In the present study, we examined the lipoproteins and receptors involved in human SMC foam cell formation and investigated the ability of 24(S),25-epoxycholesterol [24(S),25-EC], an oxysterol agonist of the liver X receptor, to attenuate SMC foam cell formation. Methods and Results-Incubation of human internal thoracic SMCs with atherogenic lipoproteins demonstrated that low-density lipoprotein (LDL), but not oxidized or acetylated LDL, was the primary lipoprotein taken up, resulting in marked cholesteryl ester deposition (6-fold vs 1.8-fold; P<0.05; n=4). Exposure of SMCs to exogenous or endogenously synthesized 24(S), 25-EC attenuated LDL uptake (-90% and -47% respectively; P<0.05; n=3) through decreased sterol regulatory element-binding protein-2 expression (-30% and -17%, respectively; P<0.001; n=3), decreased LDL receptor expression (-75% and -40%, respectively; P<0.05; n=3) and increased liver X receptor-mediated myosin regulatory light chain interacting protein expression (7- and 3-fold, respectively; P<0.05; n=4). Furthermore, exogenous 24(S), 25-EC increased adenosine triphosphate-binding cassettes A1- and G1-mediated cholesterol efflux to apolipoprotein AI (1.9-fold; P<0.001; n=5) and high-density lipoprotein(3) (1.3-fold; P<0.05; n=5). 24(S), 25-EC, unlike a nonsteroidal liver X receptor agonist, T0901317, did not stimulate sterol regulatory element-binding protein-1c-mediated fatty acid synthesis or triglyceride accumulation. 24(S), 25-EC preserved the assembly of fibronectin and type I collagen by SMCs. Conclusions-The oxysterol 24(S), 25-EC prevented foam cell formation in human SMCs by attenuation of LDL receptor-mediated LDL uptake and stimulation of cholesterol efflux, restoring the elaboration of extracellular matrix. In contrast to T0901317, 24(S), 25-EC prevented the development of a triglyceride-rich foam cell phenotype.