ABCG1 and endothelial function

ABCG1 和内皮功能

• 批准号: 8207861
• 负责人: ALAN richard TALL
• 金额: $ 40.25万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-03 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8207861
• 关键词: 7-ketocholesterol; ATP-Binding Cassette Transporters; Animal Model; Antiatherogenic; Apolipoprotein A-I; Apolipoprotein E; Apolipoproteins; Arterial Fatty Streak; Atherosclerosis; Biological Availability; Breeding; Calmodulin; Caveolae; Caveolins; Cell Adhesion Molecules; Cell model; Cells; Characteristics; Cholesterol; Complex; Data; Defect; Diet; Endothelial Cells; Endothelium; Functional disorder; Gene Transfer Techniques; Generations; Genetic Recombination; High Density Lipoproteins; Human; Inflammatory; Infusion procedures; Knock-out; Link; Mediating; Mus; NADPH Oxidase; Plasma; Play; Relaxation; Resistance; Role; Signal Transduction; Small Interfering RNA; Sterols; Testing; Transgenes; atherogenesis; cadherin 5; caveolin 1; chemokine; cytokine; feeding; human NOS3 protein; improved; in vivo; insight; knock-down; novel; overexpression; particle; protective effect; reconstitution; research study; unpublished works

Plasma high density lipoproteins (HDL) have a protective effect in atherosclerosis but the underlying mechanisms are incompletely understood. A part of the athero-protective effect of HDL may be related to its ability to reverse endothelial dysfunction, a characteristic feature of early atherosclerotic lesions involving decreased bioavailability of eNOS-derived NO and increased expression of cell adhesion molecules and inflammatory chemokines and cytokines. Many of the beneficial effects of HDL appear to be related to its ability to promote efflux of cholesterol and toxic oxysterols from cells via the ATP binding cassette transporters, ABCA1 and ABCG1. ABCG1 is highly expressed in endothelial cells and has an essential role in promoting efflux of cholesterol and 7- oxysterols to HDL. Our recent studies show that high cholesterol diet-fed Abcg1-/- develop a severe defect in eNOS-dependent relaxation of arterial segments, associated with accumulation of 7-ketocholesterol and disruption of the active, dimeric form of eNOS. In cholesterol-loaded human aortic endothelial cells (HAECs), knock-down of ABCG1 results in decreased eNOS activity and. This leads to the central hypothesis that ABCG1 has an anti-atherogenic role in endothelium. In Aim 1 we propose to investigate cellular mechanisms responsible for decreased eNOS activity and increased expression of cell adhesion molecules in ABCG1-deficient cells. The central concept we will test is whether there is increased formation of inhibitory eNOS/Caveolin complexes, increased caveolar localization and activation of signaling complexes involving NADPH oxidases. In Aims 2 and 3 we will use recently developed Abcg1flox/flox mice to carry out endothelial- specific knock-out of ABCG1. These mice will be crossed with Ldlr-/- mice to determine whether there is reduced eNOS activity, increased expression of cell adhesion molecules and increased atherogenesis. We will also determine if these mice are resistant to the athero-protective effects of increased HDL levels induced by infusions of reconstituted HDL or apoA-1 transgenesis. These studies will use novel animal and cellular models to provide new insights into the mechanisms of athero-protective effects of HDL involving arterial endothelium.

血浆高密度脂蛋白（HDL）在动脉粥样硬化中具有保护作用， 其潜在机制尚未完全了解。动脉粥样硬化保护的一部分 HDL的作用可能与其逆转内皮功能障碍的能力有关， 早期动脉粥样硬化病变的特征性特征，包括生物利用度降低 eNOS衍生的NO和细胞粘附分子的表达增加， 炎性趋化因子和细胞因子。HDL的许多有益作用似乎 与其促进胆固醇和毒性氧化固醇从细胞中流出的能力有关， ATP结合盒转运蛋白ABCA 1和ABCG 1。ABCG 1高表达 在内皮细胞中，并在促进胆固醇和7- 氧化固醇与HDL的比值。我们最近的研究表明，高胆固醇饮食喂养的Abcg 1-/- 在eNOS依赖的动脉段舒张中出现严重缺陷， 随着7-酮胆固醇的积累和活性二聚体形式的破坏， eNOS。在胆固醇负载的人主动脉内皮细胞（HAECs）中， ABCG 1导致eNOS活性降低，这就引出了一个中心假设， ABCG 1在内皮中具有抗动脉粥样硬化作用。在目标1中，我们建议调查 eNOS活性降低和表达增加的细胞机制 ABCG 1缺陷细胞中的细胞粘附分子。我们将测试的中心概念是 是否存在抑制性eNOS/小窝蛋白复合物的形成增加，是否存在抑制性eNOS/小窝蛋白 小窝定位和激活涉及NADPH氧化酶的信号复合物。 在目的2和3中，我们将使用最近开发的Abcg 1flox/flox小鼠进行内皮细胞- ABCG 1的特异性敲除。将这些小鼠与Ldlr-/-小鼠杂交以确定 是否存在eNOS活性降低、细胞粘附表达增加 分子和增加动脉粥样硬化。我们还将确定这些小鼠是否 抵抗由输注以下物质诱导的HDL水平升高的动脉粥样硬化保护作用 重组HDL或apoA-1转基因。这些研究将使用新的动物和 细胞模型，为动脉粥样硬化保护作用的机制提供新的见解 高密度脂蛋白影响动脉内皮细胞。