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ABCG1 and HDL protect against endothelial dysfunction in mice fed a high-cholesterol diet
Naoki Terasaka, … , Ira J. Goldberg, Alan R. Tall
Naoki Terasaka, … , Ira J. Goldberg, Alan R. Tall
Published October 16, 2008
Citation Information: J Clin Invest. 2008;118(11):3701-3713. https://doi.org/10.1172/JCI35470.
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Research Article Cardiology Article has an altmetric score of 3

ABCG1 and HDL protect against endothelial dysfunction in mice fed a high-cholesterol diet

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Abstract

Plasma HDL levels are inversely related to the incidence of atherosclerotic disease. Some of the atheroprotective effects of HDL are likely mediated via preservation of EC function. Whether the beneficial effects of HDL on ECs depend on its involvement in cholesterol efflux via the ATP-binding cassette transporters ABCA1 and ABCG1, which promote efflux of cholesterol and oxysterols from macrophages, has not been investigated. To address this, we assessed endothelial function in Abca1–/–, Abcg1–/–, and Abca1–/–Abcg1–/– mice fed either a high-cholesterol diet (HCD) or a Western diet (WTD). Non-atherosclerotic arteries from WTD-fed Abcg1–/– and Abca1–/–Abcg1–/– mice exhibited a marked decrease in endothelium-dependent vasorelaxation, while Abca1–/– mice had a milder defect. In addition, eNOS activity was reduced in aortic homogenates generated from Abcg1–/– mice fed either a HCD or a WTD, and this correlated with decreased levels of the active dimeric form of eNOS. More detailed analysis indicated that ABCG1 was expressed primarily in ECs, and that these cells accumulated the oxysterol 7-ketocholesterol (7-KC) when Abcg1–/– mice were fed a WTD. Consistent with these data, ABCG1 had a major role in promoting efflux of cholesterol and 7-KC in cultured human aortic ECs (HAECs). Furthermore, HDL treatment of HAECs prevented 7-KC–induced ROS production and active eNOS dimer disruption in an ABCG1-dependent manner. Our data suggest that ABCG1 and HDL maintain EC function in HCD-fed mice by promoting efflux of cholesterol and 7-oxysterols and preserving active eNOS dimer levels.

Authors

Naoki Terasaka, Shuiqing Yu, Laurent Yvan-Charvet, Nan Wang, Nino Mzhavia, Read Langlois, Tamara Pagler, Rong Li, Carrie L. Welch, Ira J. Goldberg, Alan R. Tall

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Figure 7

Effects of HDL concentrations, incubation time with 7-KC, different oxysterols, and ABCG1 expression on eNOS dimer levels.

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Effects of HDL concentrations, incubation time with 7-KC, different oxys...
(A and B) Effects of HDL concentrations on eNOS dimer disruption by 7-KC. HAECs were incubated with 7-KC (10 μg/ml) and HDL (25–200 μg/ml) for 16 h. (A) Western blot for eNOS dimer and monomer. (B) Quantification of the eNOS dimer/monomer. (C and D) Effects of incubation time with 7-KC on eNOS dimer disruption. (C) Western blot for eNOS dimer and monomer. (D) Quantification of the eNOS dimer/monomer. *P < 0.05 compared with no 7-KC at same time point. (E and F) Effects of different oxysterols on eNOS dimer disruption. HAECs were incubated with 10 μg/ml cholesterol or oxysterols in the presence or absence of HDL (100 μg/ml) for 16 h. 7αOH, 7α-hydroxycholesterol; 7βOH, 7β-hydroxycholesterol; 25OH, 25-hydroxycholesterol; 27OH, 27-hydroxycholesterol. (E) Western blot for eNOS dimer and monomer. (F) Quantification of the eNOS dimer/monomer. (G and H) HAECs were transfected with scrambled, ABCG1, ABCA1, or SR-BI siRNA. Forty-eight hours after transfection, HAECs were incubated with 7-KC (10 μg/ml) in the presence or absence of HDL (100 μg/ml) for 16 h. (G) Western blot for eNOS dimer and monomer. (H) Quantification of the eNOS dimer/monomer. The results are represented as mean ± SEM of 3 individual experiments. *P < 0.05 versus control.

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