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The role of the G2A receptor in Atherosclerosis

G2A受体在动脉粥样硬化中的作用

基本信息

批准号：
8111689
负责人：
JANUSZ H KABAROWSKI
金额：
$ 36.25万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8111689
关键词：
Ablation Address Antiatherogenic Aorta Apolipoproteins Apoptosis Arterial Fatty Streak Arterial Intimas Arteries Atherosclerosis Attenuated Biological Biological Assay Bone Marrow Bone Marrow Cells Bone Marrow Stem Cell Cell Adhesion Molecules Cells Chemosensitization Chemotaxis Cholesterol Chronic Clinical Dependence Development Disease Electrospray Ionization Endothelial Cells Endothelium Enzymes Event Exhibits G-Protein-Coupled Receptors G2A receptor Genetic Goals Hepatocyte High Density Lipoprotein Cholesterol High Density Lipoproteins Hydrolysis Immunofluorescence Immunologic In Vitro Individual Infiltration Inflammation Inflammatory Knock-out Knockout Mice LDL Cholesterol Lipoproteins Laboratories Lecithin Lesion Link Lipoproteins Liquid Chromatography Liver Low Density Lipoprotein Receptor Low Density Lipoprotein oxidation Low-Density Lipoproteins Lymphocyte Lysophosphatidylcholines Lysophospholipids Manuscripts Measures Mediating Mediator of activation protein Metabolism Methods Modification Molecular Mus Penetrance Performance Phospholipase A2 Phospholipids Plasma Platelet Activating Factor Process Production Regulation Research Personnel Retroviridae Risk Factors Role Signal Transduction Site Source Specificity Staining method Stains Stimulus Testing Transplantation Western Blotting atherogenesis cell type chemokine group X secretory phospholipase A(2)hematopoietic tissue hypercholesterolemia in vivo macrophage monocyte overexpression particle programs receptor research study response scavenger receptor therapeutic development uptake vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): Atherosclerosis is a chronic inflammatory disease characterized by the accumulation and subsequent modification of low-density lipoprotein (LDL)-cholesterol particles within the arterial wall. Establishing which of the many biological effects of modified LDL demonstrable in vitro are relevant to atherogenesis in vivo, and identifying the mechanisms of action and production of the principal molecular components responsible, remain important goals in the search for new targets for therapy in atherosclerosis. Lysophosphatidylcholine (LPC) is a major product of LDL oxidation and phospholipid hydrolysis by pro-inflammatory phospholipase A2 (PLA2) enzymes. It has been proposed that a principal effect of LPC is to promote sub-endothelial macrophage recruitment into the arterial wall at atherosclerotic foci by directly attracting monocytes and activating endothelial cells. The recently identified role of the G protein-coupled receptor, G2A, as a mediator of chemotaxis to LPC has led to the proposal that this key event is promoted by G2A. Loss of G2A function in atherosclerosis-susceptible low-density lipoprotein receptor knockout (LDLR-/-) mice led to robust suppression of aortic atherosclerosis. Intimal monocyte infiltration at lesion-prone sites of the aorta was significantly suppressed in G2A-deficient LDLR-/- (G2A-/-LDLR-/-) mice. However, elevated HDL-cholesterol levels in G2A-/-LDLR-/- mice revealed possible G2A-mediated effects on lipoprotein metabolism. Thus, G2A provides a pro-atherogenic stimulus in vivo consistent with penetrance of its chemotactic action but to which alterations in lipoprotein metabolism may also contribute. We hypothesize that stimulation of sub-endothelial monocyte infiltration in response to locally generated LPC is the principal mechanism by which G2A promotes atherosclerosis in LDLR-/- mice and that this is mediated independently of G2A-expressing endothelium. We propose that modulation of HDL-cholesterol levels by G2A is due to direct effects of this receptor on macrophage cholesterol efflux and this partially contributes to its pro-atherogenic action. To address these hypotheses, we will generate chimeric LDLR-/- mice in which G2A deficiency or G2A expression is restricted to bone marrow derived cells. HDL composition and macrophage cholesterol efflux will be examined in G2A??/- and G2A-/-LDLR-/- mice to determine the cellular mechanism by which G2A modulates HDL-cholesterol levels in hypercholesterolemic LDLR-/- mice. Finally, the LPC-dependence of G2A-mediated pro-atherogenic action will be investigated by macrophage-restricted overexpression of secretory PLA2 group X in LDLR-/- mice using a macrophage-specific retrovirus. By determining the cell specificity and LPC-dependence of G2A action, these studies will provide a molecular framework for the development of therapeutic approaches to target G2A and thereby attenuate atherosclerosis.

描述(申请人提供)：动脉粥样硬化是一种慢性炎症性疾病，其特征是低密度脂蛋白(低密度脂蛋白)-胆固醇颗粒在动脉壁内积聚和随后的修饰。确定修饰的低密度脂蛋白在体外的许多生物学效应中，哪些与体内动脉粥样硬化的形成有关，以及确定作用机制和主要相关分子成分的产生，仍然是寻找治疗动脉粥样硬化的新靶点的重要目标。溶血磷脂酰胆碱(LPC)是促炎症磷脂酶A2(PLA2)催化低密度脂蛋白氧化和磷脂水解的主要产物。LPC的一个主要作用是通过直接吸引单核细胞和激活内皮细胞，促进内皮下巨噬细胞聚集到动脉粥样硬化灶的动脉壁内。最近发现的G蛋白偶联受体G2a作为LPC趋化的中介作用，导致了这一关键事件由G2a促进的说法。在动脉粥样硬化易感低密度脂蛋白受体基因敲除(LDLR-/-)小鼠中，G2A功能的丧失导致了对主动脉粥样硬化的有力抑制。在G2A缺陷的LDLR-/-(G2A-/-LDLR-/-)小鼠中，易患病变部位的动脉内膜单核细胞浸润显著受到抑制。然而，G2A-/-LDLR-/-小鼠高密度脂蛋白-胆固醇水平的升高可能揭示了G2A对脂蛋白代谢的影响。因此，G2A在体内提供了一种促动脉粥样硬化的刺激，与其趋化作用的外显性一致，但脂蛋白代谢的变化也可能对此起作用。我们假设G2A促进LDLR-/-小鼠动脉粥样硬化的主要机制是局部产生的LPC刺激内皮下单核细胞的渗透，并且这种作用不依赖于表达G2A的内皮细胞。我们认为，G2a对高密度脂蛋白-胆固醇水平的调节是由于该受体对巨噬细胞胆固醇外流的直接作用，这部分地参与了其促动脉粥样硬化的作用。为了解决这些假设，我们将产生嵌合的LDLR-/-小鼠，在其中G2A缺乏或G2A表达仅限于骨髓来源的细胞。将检测G2A？？/-和G2A-/-LDLR-/-小鼠的高密度脂蛋白组成和巨噬细胞胆固醇外流，以确定G2A调节高胆固醇血症低密度脂蛋白-/-小鼠高密度脂蛋白-胆固醇水平的细胞机制。最后，将通过使用巨噬细胞特异性逆转录病毒在LDLR-/-小鼠体内通过巨噬细胞限制性过表达PLA2组X来研究G2A介导的促动脉粥样硬化作用的LPC依赖性。通过确定G2a作用的细胞特异性和LPC依赖性，这些研究将为开发靶向G2a的治疗方法提供分子框架，从而减轻动脉粥样硬化。