Caveolin-1 in Lipoprotein Metabolism and Atherosclerosis.

Caveolin-1 在脂蛋白代谢和动脉粥样硬化中的作用。

• 批准号: 8426164
• 负责人: Carlos Fernandez Hernando
• 金额: $ 22.97万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-04 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8426164
• 关键词: Ablation; Address; Apolipoprotein E; Applications Grants; Arterial Fatty Streak; Arteries; Atherosclerosis; Binding; Biogenesis; Blood Vessels; Cardiopulmonary; Carotid Arteries; Caveolae; Cell Adhesion Molecules; Cell membrane; Cells; Cholesterol; Cholesterol Homeostasis; Coculture Techniques; Confocal Microscopy; Crossbreeding; Data; Defect; Deposition; Electron Microscopy; Endothelial Cells; Endothelium; Event; Exhibits; Flow Cytometry; Fluorescence; Fluorescence Microscopy; Genetic; Goals; High Density Lipoproteins; Human; Impairment; Infiltration; Inflammatory; Inflammatory Response; Insulin Resistance; Intercellular adhesion molecule 1; Interleukin-1; Knock-out; Knockout Mice; Label; Lesion; Leukocyte Adhesion Molecules; Leukocyte-Adhesion Receptors; Lipids; Lipoprotein Binding; Lipoproteins; Low-Density Lipoproteins; Metabolism; Molecular; Molecular Analysis; Morbidity - disease rate; Mus; NG-Nitroarginine Methyl Ester; Nitric Oxide; Predisposition; Production; Protein Tyrosine Kinase; Publishing; Regulation; Resistance; Resolution; Role; Shapes; Signal Transduction; Societies; Staging; TNF gene; Testing; Therapeutic; Tissues; Transgenic Mice; Vascular Cell Adhesion Molecule-1; Work; arginine methyl ester; base; caveolin 1; cytokine; flasks; human NOS3 protein; in vivo; inhibitor/antagonist; insight; laser capture microdissection; macrophage; monocyte; mortality; public health relevance; research study; trafficking; transcription factor

DESCRIPTION (provided by applicant): Complications from atherosclerosis represent a major cause of morbidity and mortality in Western society. The accumulation of low-density lipoprotein (LDL)-derived cholesterol and inflammatory cells in the artery wall are the initiating events that cause atherosclerosis. However, the factors that underlie the initiation of atherosclerosis are still poorly understood. Our recent data suggest that one such factor may be caveolin-1 (Cav-1), an important structural component of caveolae. Caveolae are 50-100 nm flask-shaped invaginations of plasma membrane, and Cav-1 is essential for caveolae biogenesis in several tissues, including the arterial endothelium. Physiologically, the loss of caveolae results in impairment of cholesterol homeostasis, insulin resistance, nitric oxide production (NO), and defects in cardiopulmonary and vascular function. Interestingly, mice deficient in Cav-1 exhibit resistance to atherosclerosis despite a marked proatherogenic lipid profile, suggesting that Cav-1 determines the athero-susceptibility to the vessel wall. We recently demonstrated the critical role of endothelial Cav-1 during the progression of atherosclerosis in mice. Mice were generated lacking Cav-1 and ApoE but expressing endothelial-specific Cav-1 in the double knockout background (ApoE-/-Cav-1REC). Genetic ablation of Cav-1 on the ApoE knockout background inhibited the progression of atherosclerosis, while re-expression of Cav-1 in the endothelium promoted lesion expansion. Several different mechanism appear to be involved, including reduced LDL infiltration into the artery wall, increased production of nitric oxide (NO), reduced expression of leukocyte adhesion molecules and decreased monocyte accumulation in atherosclerotic plaques. The precise mechanisms by which Cav-1 and/or caveolae controls all of these events remains unknown. Thus, a major challenge of this grant proposal is to determine the molecular mechanism by which endothelial-specific Cav-1 controls the early stages and progression of atherosclerosis. We propose three aims. Aim 1: To investigate the molecular mechanism by which Cav-1 regulates lipoprotein trafficking in the artery wall and lipid/lipoprotein metabolism in arterial endothelial cells. Aim 2: To define the role of NO in the atheroprotection observed in Cav-1 null mice. Aim 3: To define whether Cav-1 expression regulates EC inflammatory response and macrophage mobilization in vivo. In summary completion of these aims will provide insight into fundamental regulatory mechanism by which Cav-1/caveolae regulates lipoprotein metabolism and the progression of atherosclerosis.

描述(申请人提供)：动脉粥样硬化并发症是西方社会发病率和死亡率的主要原因。低密度脂蛋白(低密度脂蛋白)衍生的胆固醇和炎症细胞在动脉壁中的积聚是导致动脉粥样硬化的始动事件。然而，引发动脉粥样硬化的因素仍然知之甚少。我们最近的数据表明，其中一个因素可能是小窝蛋白-1(Cav-1)，它是小窝的一个重要结构成分。小窝是50-100 nm的瓶状质膜内陷，Cav-1在包括动脉内皮在内的多种组织中是小窝生物发生所必需的。从生理上讲，小窝的丧失会导致胆固醇稳态受损、胰岛素抵抗、一氧化氮(NO)的产生，以及心肺和血管功能的缺陷。有趣的是，Cav-1基因缺陷的小鼠表现出对动脉粥样硬化的抵抗力，尽管有明显的致动脉粥样硬化脂质特征，这表明Cav-1决定了对血管壁的动脉粥样硬化易感性。我们最近证实了内皮细胞Cav-1在小鼠动脉粥样硬化进展过程中的关键作用。在双基因敲除背景(ApoE-/-Cav-1REC)中，产生缺失Cav-1和ApoE但表达内皮特异性Cav-1的小鼠。ApoE基因敲除背景上的Cav-1基因消融抑制了动脉粥样硬化的进展，而血管内皮细胞中Cav-1的重新表达促进了病变的扩大。几种不同的机制似乎参与其中，包括减少低密度脂蛋白对动脉壁的渗透，增加一氧化氮(NO)的产生，减少白细胞黏附分子的表达，减少单核细胞在动脉粥样硬化斑块中的积聚。Cav-1和/或Caveolae控制所有这些事件的确切机制尚不清楚。因此，这项拨款提案的一个主要挑战是确定内皮特异性Cav-1控制动脉粥样硬化早期阶段和进展的分子机制。我们提出了三个目标。目的1：探讨Cav-1调节动脉壁脂蛋白转运和动脉内皮细胞脂/脂蛋白代谢的分子机制。目的2：明确NO在Cav-1基因缺失小鼠动脉粥样硬化保护中的作用。目的：明确Cav-1在体内是否调节内皮细胞炎症反应和巨噬细胞动员。总之，这些目标的完成将有助于深入了解Cav-1/Caveolae调节脂蛋白代谢和动脉粥样硬化进展的基本调控机制。