ATP-Binding Cassette Transporter G1 and High-Density Lipoprotein Promote Endothelial NO Synthesis Through a Decrease in the Interaction of Caveolin-1 and Endothelial NO Synthase

• DOI: 10.1161/atvbaha.110.213215
• Publication Date: 2010-08-27T02:59:21Z
• Authors: Naoki Terasaka; Marit Westerterp; Joris Koetsveld; Carlos Fernández...; Laurent Yvan-Charvet; Nan Wang; William C. Sessa; Alan R. Tall
• Keywords: Member 1; Nitric Oxide Synthase Type III; ATP Binding Cassette Transporter; Nitric Oxide/biosynthesis; Caveolin 1; Cholesterol, HDL; Nitric Oxide Synthase Type III/metabolism; Endothelial Cells; Caveolin 1/metabolism; Subfamily G; Nitric Oxide; Mice; 03 medical and health sciences; Cholesterol; 0302 clinical medicine; Animals; Humans; ATP-Binding Cassette Transporters; ATP-Binding Cassette Transporters/metabolism; HDL/metabolism; ATP Binding Cassette Transporter, Subfamily G, Member 1

Objective—

To investigate whether cholesterol efflux to high-density lipoprotein (HDL) via ATP-binding cassette transporter G1 (ABCG1) modulates the interaction of caveolin (Cav) 1 and endothelial NO synthase (eNOS).

Methods and Results—

ABCG1 promotes cholesterol and 7-oxysterol efflux from endothelial cells (ECs) to HDL. It was previously reported that ABCG1 protects against dietary cholesterol-induced endothelial dysfunction by promoting the efflux of 7-oxysterols to HDL. Increased cholesterol loading in ECs is known to cause an inhibitory interaction between Cav-1 and eNOS and impaired NO release. In human aortic ECs, free cholesterol loading promoted the interaction of Cav-1 with eNOS, reducing eNOS activity. These effects of cholesterol loading were reversed by HDL in an ABCG1-dependent manner. HDL also reversed the inhibition of eNOS by cholesterol loading in murine lung ECs, but this effect of HDL was abolished in Cav-1–deficient murine lung ECs. Increased interaction of Cav-1 with eNOS was also detected in aortic homogenates of high-cholesterol diet–fed Abcg1 −/− mice, paralleling a decrease in eNOS activity and impaired endothelial function.

Conclusion—

The promotion of cholesterol efflux via ABCG1 results in a reduced inhibitory interaction of eNOS with Cav-1.