Resistin promotes macrophage foam cell formation in rats via dysregulation of scavenger receptors and ATP‐binding cassette transporters

Abstract

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.