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.

Dyslipidemia and the risk of incident hypertension in a population of community-dwelling Brazilian elderly: the Bambuí cohort study of aging

“…Low serum HDL-C levels contributed to structural and functional alterations which led to arterial rigidity 35 . Studies carried out in animal models 37 and humans 38 showed that low HDL-C levels are associated with significant endothelial dysfunction and compromised peripheral vasodilatation. In autopsies of elderly Japanese women, it was observed that serum HDL-C levels were inversely associated with atherosclerosis of medium and large arteries 39 .…”

HDL abnormalities in nephrotic syndrome and chronic kidney disease

“…HDL enhances endothelial function through the activation of endothelial nitric oxide synthase (eNOS), which increases the production of nitric oxide. This process is achieved by Akt-mediated phosphorylation of eNOS upon HDL binding to its receptors, SRB1 and S1P3 [14][15][16] . The antioxidant activity of HDL can also limit the uncoupling of eNOS and inactivation of nitric oxide by inhibiting the production of reactive oxygen species (ROS) by binding ABCG1 (FIG.…”

Dietary cholesterol and egg yolks: Not for patients at risk of vascular disease

“…Postprandial levels of lipids are at least as predictive of risk as fasting lipid levels (26,27); the difficulty is in standardizing the conditions in which they are measured. In mouse models, both a western diet and a high-cholesterol diet induce endothelial dysfunction (28). In human subjects, endothelial function is impaired for approximately 4 h after consumption of a high-fat/high-cholesterol meal; this effect is probably due to oxidative stress (29), because the effect is mitigated by the antioxidant supplements (30).…”