title: Endothelin-1 exacerbates lipid accumulation by increasing the protein degradation of the ATP-binding cassette transporter G1 in macrophages.
abstract: 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.
authors.affiliation: Institute of Physiology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chun-Yueh
authors.initials: CY
authors.lastname: Lin
authors.forename: Tzong-Shyuan
authors.initials: TS
authors.lastname: Lee
authors.forename: Chin-Chang
authors.initials: CC
authors.lastname: Chen
authors.forename: Cheng-An
authors.initials: CA
authors.lastname: Chang
authors.forename: Yan-Jie
authors.initials: YJ
authors.lastname: Lin
authors.forename: Yung-Pei
authors.initials: YP
authors.lastname: Hsu
authors.forename: Low-Tone
authors.initials: LT
authors.lastname: Ho
mesh_terms: D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D002154:Calpain / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism* / Q000494:pharmacology; D005786:Gene Expression Regulation; D050356:Lipid Metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology; D008264:Macrophages / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism
chemical_list: D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; C559724:Abcg1 protein, rat; D019332:Endothelin-1; D008077:Lipoproteins, LDL; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C099252:oxidized low density lipoprotein; D058539:Phosphatidylinositol 3-Kinase; D002154:Calpain; D046988:Proteasome Endopeptidase Complex