ABCG1 Deficiency in Mice Promotes Endothelial Activation and Monocyte–Endothelial Interactions

Abstract

Objective-Activated endothelium and increased monocyte-endothelial interactions in the vessel wall are key early events in atherogenesis. ATP binding cassette (ABC) transporters play important roles in regulating sterol homeostasis in many cell types. Endothelial cells (EC) have a high capacity to efflux sterols and express the ABC transporter, ABCG1. Here, we define the role of ABCG1 in the regulation of lipid homeostasis and inflammation in aortic EC. Methods and Results-Using EC isolated from ABCG1-deficient mice (ABCG1 KO), we observed reduced cholesterol efflux to high-density lipoprotein compared to C57BL/6 (B6) EC. However, total cholesteryl ester levels were not changed in ABCG1 KO EC. Secretions of KC, MCP-1, and IL-6 by ABCG1 KO EC were significantly increased, and surface expressions of intercellular adhesion molecule-1 and E-selectin were increased several-fold on ABCG1 KO EC. Concomitant with these findings, we observed a 4-fold increase in monocyte adhesion to the intact aortic endothelium of ABCG1 KO mice ex vivo and to isolated aortic EC from these mice in vitro. In a gain-of-function study in vitro, restoration of ABCG1 expression in ABCG1 KO EC reduced monocyte-endothelial interactions. Utilizing pharmacological inhibitors for STAT3 and the IL-6 receptor, we found that blockade of STAT3 and IL-6 receptor signaling in ABCG1 KO EC completely abrogated monocyte adhesion to ABCG1 KO endothelium. Key Words: ABC transporters Ⅲ endothelial Ⅲ monocyte adhesion A key early event in atherosclerosis is the increased interaction of monocytes with endothelial cells (EC) in the vessel wall. 1 In early atherogenesis, EC in the artery wall become activated, in many cases by oxidized lipids. Activated EC secrete proinflammatory chemokines that recruit monocytes to the activated endothelium. Interaction of monocytes with adhesion molecules and integrins on the endothelial surface causes the monocytes to tether and firmly adhere to the endothelium, where they can subsequently transmigrate into the subendothelial space. [2][3][4] ABCG1 is an ATP-binding cassette transporter that has been well-studied in macrophages. ABCG1 has been shown to promote cholesterol efflux to high-density lipoprotein (HDL) particles in reverse cholesterol transport. 5,6 Deficiency of ABCG1 in macrophages leads to reduced cholesterol efflux and increased macrophage cholesteryl ester accumulation. 5,6 Rader et al 7 have elegantly shown that ABCG1 promotes reverse cholesterol transport in mice in vivo. We previously reported that ABCG1 expression and function are significantly reduced in patients with type 2 diabetes, potentially contributing to the formation of lipid-laden macrophages and accelerated atherosclerosis in these patients. 8 Aortic EC also express the ABC transporters ABCA1 and ABCG1 and efflux cholesterol to HDL. 9 EC have a dramatic ability to efflux cholesterol, most likely to aid in homeostasis to prevent endothelial activation in the vessel wall. 9,10 There is tight regulation of sterol content and ABC transporter expressi...

Nascent HDL formation in hepatocytes and role of ABCA1, ABCG1, and SR-BI

“…Because ABCG1 has a synergistic effect with ABCA1 in promoting cellular cholesterol effl ux, ABCG1 may also play a role in HDL biogenesis. Studies on ABCG1 in promoting cholesterol effl ux have been largely investigated in macrophages ( 19,45 ) and endothelial cells ( 46,47 ). In hepatocytes, we showed ABCG1 gene expression which is highly upregulated by LXR.…”

Cardioprotective functions of HDLs

“…The rHDL-induced expression of DHCR24 in cultured endothelial cells is dependent on SR-B1, but not on ABCA1 or ABCG1 ( 87 ). This effect appears not to be related to the ability of SR-B1, ABCA1, or ABCG1 to maintain intracellular cholesterol homeostasis but, rather, is associated with the activation of intracellular signal transduction pathways that are involved in infl ammation (89)(90)(91).…”

ATP-Binding Cassette Transporters, Atherosclerosis, and Inflammation

“…141 Increased HDL levels achieved by expression of the human APOA1 transgene reversed the increased macrophage colonystimulating factor, MCP-1, and granulocyte colony-stimulating factor and the associated monocytosis and neutrophilia, 16 indicating that HDL also suppresses inflammation independent of the ABC transporters. 130,131 Thus, macrophage cholesterol efflux pathways mediated by ABCA1, ABCG1, and HDL suppress inflammation and the resulting monocytosis and neutrophilia.…”

“…130 Abcg1 −/− endothelial cells have been shown to exhibit increased secretion of MCP-1 and IL-6 as well as increased surface expression of intracellular adhesion molecule-1 and E-selectin concomitant with a 4-fold increase in monocyte adhesion (Figure 2, step D). 131 The decreased endothelial NO synthase (eNOS) activity on Abcg1 deficiency may have been attributable in part to accumulation of oxysterols and cholesterol. 127,132 7-Ketocholesterol accumulation in endothelial cells was shown to generate reactive oxygen species that combined with NO to form peroxynitrite, which disrupts eNOS dimers that are required for its activity.…”