Endothelin-1 (ET-1), a potent proatherogenic vasoconstrictive peptide, is known to promote macrophage foam cell formation via mechanisms that are not fully understood. Excessive lipid accumulation in macrophages is a major hallmark during the early stages of atherosclerotic lesions. Cholesterol homeostasis is tightly regulated by scavenger receptors (SRs) and ATP-binding cassette (ABC) transporters during the transformation of macrophage foam cells. The aim of this study was to investigate the possible mechanisms by which ET-1 affects lipid accumulation in macrophages. Our results demonstrate that oxidized low-density lipoprotein (oxLDL) treatment increases lipid accumulation in rat bone marrow-derived macrophages. Combined treatment with ET-1 and oxLDL significantly exacerbated lipid accumulation in macrophages as compared to treatment with oxLDL alone. The results of Western blotting show that ET-1 markedly decreased the ABCG1 levels via ET type A and B receptors and activation of the phosphatidylinositol 3-kinase pathway; however, ET-1 had no effect on the protein expression of CD36, SR-BI, SR-A, or ABCA1. In addition, real-time PCR analysis showed that ET-1 treatment did not affect ABCG1 mRNA expression. We also found that ET-1 decreases ABCG1 possibly due to the enhancement of the proteosome/calpain pathway-dependent degradation of ABCG1. Moreover, ET-1 significantly reduced the efficiency of the cholesterol efflux in macrophages. Taken together, these findings suggest that ET-1 may impair cholesterol efflux and further exacerbate lipid accumulation during the transformation of macrophage foam cells.

We studied the cellular mechanisms underlying the acceleration effect of resistin on macrophage foam cell formation. In vivo studies demonstrated that resistin levels were elevated in atherosclerotic aortas of apolipoprotein E deficient mice compared with wildtype counterparts. In vitro studies showed that resistin increased lipid accumulation in rat macrophages treated with oxidized low‐density lipoprotein (oxLDL), as compared to control cells. Resistin also increased levels of mRNA and proteins of scavenger receptor class A (SR‐A) and CD36 (two types of SRs for internalization of oxLDL) and decreased protein level, but not mRNA level, of ATP‐binding cassette transporter‐A1 (ABCA1; a type of cholesterol exporter). The up‐regulations of SR‐A and CD36 by resistin were due to activation of AP‐1 and PPARγ, respectively, as evidenced by increased nuclear levels of these two transcriptional factors and by their preventions after pharmacological inhibition of AP‐1 (curcumin or SP600125) or PPARγ (GW9662). The down‐regulation of ABCA1 by resistin resulted from a more rapid degradation of protein via proteasome pathway, as revealed by its abolition after pharmacological inhibition (calpeptin or MG‐132) of the pathway. In conclusion, resistin may promote foam cell formation via dsyregulation of SR‐A, CD36 and ABCA1. SR‐A and CD36 are up‐regulated through transcription regulation, whereas ABCA1 is down‐regulated through proteasome‐mediated protein degradation.