GPCR Signaling and Vascular Wall Remodeling

GPCR 信号传导和血管壁重塑

• 批准号: 9193490
• 负责人: GADIPARTHI N RAO
• 金额: $ 45.19万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9193490
• 关键词: ARHGEF1 gene; ATF2 gene; ATP binding cassette transporter 1; ATP-Binding Cassette Transporters; Address; Apolipoprotein E; Applications Grants; Arterial Fatty Streak; Atherosclerosis; Attenuated; Blood Platelets; Blood Vessels; Blood coagulation; CD36 gene; Cause of Death; Chemotactic Factors; Cholesterol; Chronic Disease; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Data; Dissociation; Dominant-Negative Mutation; Dose; EMSA; Endothelial Cells; Environmental Risk Factor; Event; Fibroblasts; Foam Cells; Functional disorder; Funding; G Protein-Coupled Receptor Signaling; Genetic Risk; Inflammation; Knowledge; Lesion; Link; Luciferases; Mediating; Messenger RNA; Mitogens; Mus; Myocardial Infarction; PAR-1 Receptor; Pathogenesis; Peritoneal Macrophages; Play; Proteinase-Activated Receptors; Proteins; PubMed; Regulatory Element; Reporting; Role; Serine Protease; Signal Transduction; Site-Directed Mutagenesis; Small Interfering RNA; Smooth Muscle Myocytes; Societies; Stroke; Testing; Thrombin; Thrombosis; Thrombus; Time; Ubiquitination; Vascular Diseases; Vascular Smooth Muscle; atherogenesis; atherothrombosis; base; cell type; cholesterol transporters; chromatin immunoprecipitation; cullin-3; feeding; insight; macrophage; migration; monocyte; mortality; novel; overexpression; oxidized lipid; oxidized low density lipoprotein; promoter; receptor; research study; response; scaffold; scavenger receptor; ubiquitin-protein ligase; uptake; western diet

Atherosclerosis is a chronic disease of arterial wall caused by various genetic and environmental risk factors and is the foremost cause of mortality worldwide. Inflammation plays a critical role in atherogenesis. Protease- activated receptor 1 (Par1) that mediates the cellular effects of thrombin, a serine protease, has been reported to play an important role in inflammation. In addition, a large body of data suggests that Par1 plays an essential role in atherothrombosis. Despite the role of Par1 in inflammation and atherothrombosis and the fact that increased expression of Par1 is observed in atherosclerotic plaques, nothing is known about its role in atherogenesis. In this context, we recently discovered that thrombin induces the expression of CD36, a scavenger receptor linked to oxLDL uptake and foam cell formation, and this event requires Gα12/13, Pyk2, Gab1, PKCθ and ATF2 activation downstream to Par1. In addition, we found that thrombin induces the depletion of ABCA1, a reverse cholesterol transporter and attenuates cholesterol efflux. Interestingly, ABCA1 was found to exist in complex with GSK3β and, upon treatment with thrombin, it dissociates from GSK3β, associates with cullin 3, a component of E3 ligases, and undergoes degradation. Based on these novel observations, we hypothesize that thrombin-Par1 axis plays a major role in atherogenesis. To test this central hypothesis, we propose to address the following three specific aims: Specific Aim 1: Par1 plays a central role in atherogenesis. Specific Aim 2: PKCθ via activating ATF2 and enhancing CD36 expression, oxLDL uptake and foam cell formation plays a crucial role in atherogenesis. Specific Aim 3: Overexpression of GSK3β stabilizes ABCA1, enhances cholesterol efflux and protects from atherogenesis. The results of the proposed studies will provide new mechanistic insights into the pathophysiology of atherosclerosis and explore the translational impact of thrombin-Par1 signaling in this debilitating vascular disease.

动脉粥样硬化是一种由多种遗传和环境危险因素引起的动脉壁慢性疾病 也是全世界死亡的首要原因。炎症在动脉粥样硬化形成中起着关键作用。蛋白酶- 已经报道了介导凝血酶（一种丝氨酸蛋白酶）的细胞效应的活化受体1（Par 1 在炎症中发挥重要作用。此外，大量的数据表明，Par 1发挥了 在动脉粥样硬化血栓形成中的重要作用。尽管Par 1在炎症和动脉粥样硬化血栓形成中的作用， 尽管在动脉粥样硬化斑块中观察到Par 1表达增加，但关于其在动脉粥样硬化斑块中的作用尚不清楚。 动脉粥样硬化在这种情况下，我们最近发现凝血酶诱导CD 36的表达， 清道夫受体与oxLDL摄取和泡沫细胞形成有关，这一事件需要Gα12/13，Pyk 2， 在Par 1下游激活Gab 1、PKCθ和ATF 2。此外，我们发现凝血酶诱导了 消耗ABCA 1，一种反向胆固醇转运蛋白，并减弱胆固醇流出。有趣的是，ABCA 1 发现存在于与GSK 3 β的复合物中，并且在用凝血酶处理后，其与GSK 3 β解离， 与cullin 3（E3连接酶的组分）缔合并经历降解。根据这些小说 通过观察，我们假设凝血酶-Par 1轴在动脉粥样硬化形成中起主要作用。为了测试这个中央 假设，我们建议解决以下三个具体目标：具体目标1：Par 1发挥核心作用 在动脉粥样硬化形成中。具体目的2：PKCθ通过激活ATF 2和增强CD 36表达，oxLDL摄取 泡沫细胞的形成在动脉粥样硬化形成中起着关键作用。具体目标3：GSK 3 β的过表达 稳定ABCA 1，增强胆固醇流出并防止动脉粥样硬化形成。建议的结果 这些研究将为动脉粥样硬化的病理生理学提供新的机制见解， 凝血酶-Par 1信号转导在这种衰弱性血管疾病中的翻译影响。