Caveolin-1 in Lipoprotein Metabolism and Atherosclerosis.

描述（由申请人提供）：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（LDL）衍生的胆固醇和炎性细胞在动脉壁中的积聚是导致动脉粥样硬化的起始事件。然而，动脉粥样硬化发生的基础因素仍然知之甚少。我们最近的数据表明，这样一个因素可能是小窝蛋白-1（Cav-1），一个重要的结构组成部分的小窝。 小窝是质膜的50-100 nm烧瓶状内陷，Cav-1是包括动脉内皮在内的几种组织中小窝生物发生所必需的。在生理上，小窝的丧失导致胆固醇稳态、胰岛素抵抗、一氧化氮产生（NO）的损害以及心肺和血管功能的缺陷。有趣的是，Cav-1缺陷的小鼠表现出对动脉粥样硬化的抵抗，尽管有显著的致动脉粥样硬化脂质谱，这表明Cav-1决定了血管壁的动脉粥样硬化易感性。我们最近证明了内皮细胞Cav-1在小鼠动脉粥样硬化进展过程中的关键作用。产生缺乏Cav-1和ApoE但在双敲除背景中表达内皮特异性Cav-1的小鼠（ApoE-/-Cav-1 REC）。在ApoE基因敲除的背景下，Cav-1的基因消融抑制了动脉粥样硬化的进展，而Cav-1在内皮中的重新表达促进了病变的扩大。几种不同的机制似乎涉及，包括减少LDL浸润到动脉壁中，增加一氧化氮（NO）的产生，减少白细胞粘附分子的表达和减少单核细胞在动脉粥样硬化斑块中的积聚。Cav-1和/或小窝控制所有这些事件的确切机制仍然未知。因此，这项拨款提案的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。我们提出三个目标。目标1：探讨Cav-1调控脂蛋白在动脉壁运输和动脉内皮细胞脂质/脂蛋白代谢的分子机制。目的2：探讨NO在Cav-1基因敲除小鼠动脉粥样硬化保护中的作用。目的3：研究Cav-1表达对EC炎症反应和巨噬细胞动员的影响.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节机制。 公共卫生相关性：低密度脂蛋白（LDL）衍生的胆固醇和炎性细胞在动脉壁中的积聚是导致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蛋白-1（Cav-1），一个重要的结构组成部分的小窝。该提案的主要目标是研究Cav-1调节脂蛋白代谢和动脉粥样硬化进展的机制。这项工作将提供关键的洞察基本的调节机制，并可能确定潜在的治疗策略，通过调节Cav-1的表达，调节脂蛋白和炎性细胞浸润的动脉壁。

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.