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。

基本信息

批准号：
8023626
负责人：
Carlos Fernandez Hernando
金额：
$ 42.25万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-04 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8023626
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 research study trafficking transcription factor

项目摘要

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. PUBLIC HEALTH RELEVANCE: The accumulation of low-density lipoprotein (LDL)-derived cholesterol and inflammatory cells in the artery wall are the initiating events that cause atherosclerosis. Our recent data suggest that one such factor may be caveolin-1 (Cav-1), an important structural component of caveolae. The proposal main goal is to investigate the mechanism by which Cav-1 regulates lipoprotein metabolism and the progression of atherosclerosis. This work will provide critical insight into fundamental regulatory mechanism and may indentify potential therapeutic strategies for the regulation of the lipoprotein and inflammatory cell infiltration in the artery wall through modulation of Cav-1 expression.

描述（由申请人提供）：动脉粥样硬化的并发症代表了西方社会发病率和死亡率的主要原因。低密度脂蛋白（LDL）衍生的胆固醇和动脉壁中炎症细胞的积累是引起动脉粥样硬化的起始事件。但是，动脉粥样硬化启动的基础的因素仍然很少了解。我们最近的数据表明，这样一个因素可能是小窝1（CAV-1），这是小窝的重要结构成分。小窝是质膜的50-100 nm烧瓶形，CAV-1对于包括动脉内皮在内的多个组织中的小窝生物发生至关重要。从生理上讲，口腔的丧失导致胆固醇稳态，胰岛素抵抗，一氧化氮产生（NO）以及心肺和血管功能的缺陷受损。有趣的是，尽管有明显的促进性脂质谱图，但缺乏CAV-1的小鼠对动脉粥样硬化表现出抗性动脉粥样硬化，这表明CAV-1决定了对血管壁的动脉粥样硬化性。我们最近证明了内皮CAV-1在小鼠动脉粥样硬化进展过程中的关键作用。在双敲除背（apoE-/ - cav-1rec）中产生缺乏CAV-1和APOE的小鼠，但表达内皮特异性CAV-1。 Cav-1在APOE敲除背景上的遗传消融抑制了动脉粥样硬化的进展，而内皮中CAV-1的重新表达促进了病变的扩张。似乎涉及几种不同的机制，包括减少LDL浸润到动脉壁，一氧化氮（NO）的产生增加，白细胞粘附分子的表达降低以及动脉粥样硬化斑块中单核细胞的积累降低。 Cav-1和/或Caveolae控制所有这些事件的确切机制仍然未知。因此，该赠款建议的主要挑战是确定内皮特异性CAV-1控制动脉粥样硬化的早期和进展的分子机制。我们提出了三个目标。目的1：研究CAV-1通过动脉内皮细胞中动脉壁和脂质/脂蛋白代谢的脂蛋白运输的分子机制。目标2：定义NO在Cav-1 Null小鼠中观察到的动脉保护中的作用。目标3：定义CAV-1表达是否调节体内炎症反应和巨噬细胞动员。总而言之，这些目标的完成将提供有关CAV-1/Caveolae调节脂蛋白代谢和动脉粥样硬化进展的基本调节机制的见解。公共卫生相关性：低密度脂蛋白（LDL）衍生的胆固醇和炎症细胞的积累是引起动脉粥样硬化的起始事件。我们最近的数据表明，这样一个因素可能是小窝1（CAV-1），这是小窝的重要结构成分。提议的主要目标是研究CAV-1调节脂蛋白代谢和动脉粥样硬化进展的机制。这项工作将为基本调节机制提供批判性的见解，并可以通过调节CAV-1表达来调节动脉壁中脂蛋白和炎症细胞浸润的潜在治疗策略。