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

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

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 1

Response to vasoconstrictive agents in the femoral arteries from control (WT), Abcg1–/–, Abca1–/–, and Abca1–/–Abcg1–/– mice.

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Response to vasoconstrictive agents in the femoral arteries from control...
(A–C) WT and Abcg1–/– mice (n = 4 per group) were put on a HCD (1.25% cholesterol, 7.5% cocoa butter and 0.5% sodium cholate) for 11 weeks. (A) Original trace recordings showing vessel tension increase after addition of 3 μM phenylephrine (PE) and relaxation in response to different concentrations of ACh. ACh-induced vasorelaxation occurred at the indicated concentrations in control and Abcg1–/– mice. (B) Vasorelaxation in response to ACh was markedly attenuated in Abcg1–/– mice. (C) There was no significant difference in relaxation in response to SNP. (D and E) WT and Abcg1–/– mice (n = 5 per group) were put on a chow diet. There was no difference between the groups in the response to ACh (D) or SNP (E). (F and G) WT, Abcg1–/–, Abca1–/–, and Abca1–/–Abcg1–/– (n = 5 per group) were put on a WTD (0.25% cholesterol and 21% milk fat) for 12 weeks. (F) There was a similar severe defect in vascular relaxation response to ACh in Abcg1–/– and Abca1–/–Abcg1–/– mice, while the response of Abca1–/– mice was intermediate between these groups and the controls. (G) There was no significant difference in relaxation in response to SNP. The results are represented as mean ± SEM.