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.

Visfatin Promotes Foam Cell Formation by Dysregulating Cd36, Sra, Abca1, and Abcg1 Expression in RAW264.7 Macrophages

“…According to previous studies, proteasome-and lysosomemediated degradation are the major pathways responsible for ABCA1 and ABCG1 protein stability (32)(33)(34)(35). The present study found that visfatin caused protein instability of ABCG1 through the proteasome-mediated degradation pathway (Fig.…”

Emerging roles of calpain proteolytic systems in macrophage cholesterol handling

“…Accordingly, transgenic Cast over-expression upregulates the expression of ABCA1 protein in cultured macrophages in the presence of acetylated LDL [49]. It is noteworthy that calpain inhibitors can oppose the proteolytic degradation of ABCA7 [78] and ABCG1 [79] in cultured macrophages. In addition to the ABC transporters, conventional calpains appear to proteolyze liver X receptor a (LXRa), a sterolsensitive transcriptional factor in macrophages.…”

Calpain and Atherosclerosis

“…Upon exposure of macrophages to apoA-I, binding of apoA-I to ABCA1 accelerated cholesterol efflux and inhibited calpain-mediated degradation of ABCA1. Lin et al demonstrated that endothelin-1 treatment of oxidized LDL-stimulated rat bone marrow-derived macrophages leads to proteolytic degradation of ATPbinding cassette transporter G1 (ABCG1) by calpain, with no alteration of CD36 protein expression, scavenger receptor class B type I or scavenger receptor class A or ABCA1, which resulted in accelerating cholesterol accumulation in the cells 11) . Therefore, calpains are capable of interfering with cholesterol efflux from monocytes/macrophages via degradation of the ABC transporters; however, the actions of calpains in these cells or active constituents in plasma.…”

“…As a result of these calpain-regulated inflammatory responses in ECs, monocytes/macrophages are recruited into the intimal space, and subsequently scavenge the accumulated LDLs. During LDL processing, μ-calpain appears to proteolytically inactivate ABC transporters in macrophages 8,11) , resulting in further enhancement of cholesterol accumulation and foam cell formation. Thus, it is likely that the calpain systems in ECs and monocytes/macrophages have significant roles in the development of atherosclerotic lesions.…”

“…Furthermore, the deleterious effects of calpains under conditions of cardiovascular disease, including hypertension 4) and diabetes mellitus 5,6) , have been proposed. Recently, several lines of evidence published by us 7) and others [8][9][10][11][12] indicated pathophysiological implications of calpain systems in atherosclerotic diseases, although calpains are likely to participate in the physiological regulation of the vessels 13) . Accordingly, this review highlights the physiological roles of calpain systems, as well as their proatherogenic properties.…”