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.

动脉粥样硬化是由各种遗传和环境风险因素引起的动脉壁的慢性疾病 这是全球死亡率的首要原因。炎症在动脉粥样硬化中起关键作用。蛋白酶 - 已经报道了介导凝血酶（丝氨酸蛋白）细胞作用的活化受体1（PAR1） 在炎症中发挥重要作用。此外，大量数据表明PAR1扮演 在动脉粥样硬化中的重要作用。尽管PAR1在炎症和动脉粥样硬化中的作用以及事实 在动脉粥样硬化斑块中观察到PAR1的表达增加，对其在 动脉粥样硬化。在这种情况下，我们最近发现凝血酶诱导CD36的表达 与OXLDL摄取和泡沫细胞形成相关的清除剂接收器，此事件需要Gα12/13，Pyk2， GAB1，PKCθ和ATF2激活下游至PAR1。此外，我们发现凝血酶诱导了 ABCA1的耗竭，一种反向胆固醇转运蛋白并减弱胆固醇外排。有趣的是，ABCA1 被发现与GSK3β复合物存在，并在用凝血酶治疗后，它与GSK3β分离， 与E3连接酶的组成部分Cullin 3相关，并经历降解。基于这些小说 观察结果，我们假设凝血酶PAR1轴在动脉粥样硬化中起主要作用。测试这个中央 假设，我们建议解决以下三个特定目的：特定目标1：PAR1起着核心作用 特定的目标2：通过激活ATF2并增强CD36表达，OXLDL吸收，PKCθ 泡沫细胞的形成在动脉粥样硬化中起着至关重要的作用。特定目标3：GSK3β的过表达 稳定ABCA1，增强胆固醇外排并保护动脉粥样硬化。提议的结果 研究将为动脉粥样硬化的病理生理提供新的机械见解，并探索 凝血酶PAR1信号传导在这种衰弱的血管疾病中的翻译影响。