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

作者：Whetzel Angela M; Sturek Jeffrey M; Nagelin Melissa H; Bolick David T; Gebre Abraham K; Parks John S; Bruce Anthony C; Skaflen Marcus D; Hedrick Catherine C^*

来源：Arteriosclerosis, Thrombosis, and Vascular Biology, 2010, 30(4): 809-U390.

DOI：10.1161/ATVBAHA.109.199166

• ABC transporters
• endothelial
• monocyte adhesion

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.
Conclusion-ABCG1 deficiency in aortic endothelial cells activates endothelial IL-6-IL-6 receptor-STAT3 signaling, thereby increasing monocyte-endothelial interactions and vascular inflammation. (Arterioscler Thromb Vasc Biol. 2010; 30: 809-817.)

• 出版日期2010-4