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Endothelin‐1 exacerbates lipid accumulation by increasing the protein degradation of the ATP‐binding cassette transporter G1 in macrophages
Author(s) -
Lin ChunYueh,
Lee TzongShyuan,
Chen ChinChang,
Chang ChengAn,
Lin YanJie,
Hsu YungPei,
Ho LowTone
Publication year - 2011
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.22556
Subject(s) - abcg1 , abca1 , cd36 , scavenger receptor , foam cell , chemistry , microbiology and biotechnology , receptor , lipid metabolism , macrophage , cholesterol , biochemistry , transporter , lipoprotein , biology , in vitro , gene
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. J. Cell. Physiol. 226: 2198–2205, 2011. © 2010 Wiley‐Liss, Inc.