Adenosine Receptors and Atherogenesis

腺苷受体和动脉粥样硬化形成

基本信息

批准号：
8235840
负责人：
KATYA RAVID
金额：
$ 40.22万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8235840
关键词：
Ablation Address Adenosine Adenylate Cyclase Adhesions Affect Affinity Age Apolipoprotein E Atherosclerosis Attention Balloon Angioplasty Binding Blood Vessels Bone Marrow Bone Marrow Cells Bone Marrow Transplantation CXCR4 gene Cells Coronary Data Development Diet Fatty acid glycerol esters Functional disorder Gelatinase B Gene Activation Gene Deletion Gene Expression Gene Expression Regulation Genes Homeostasis Human Inflammation Inflammatory Inflammatory Response Injury Investigation Ischemia Knock-in Mouse Knock-out Knockout Mice Lead Lesion Leukocytes Ligands Light Mediating Messenger RNA Metalloproteases Mus Nuclear Pathogenesis Pathology Phenotype Play Process Production Proteins Purinergic P1 Receptors Receptor Activation Receptor Gene Regulation Relative (related person)Reporter Genes Reporting Research Research Proposals Role Signal Transduction Smooth Muscle Myocytes Stress Stromal Cell-Derived Factor 1 TNF gene Therapeutic Agents Tumor Necrosis Factor-alpha Up-Regulation Vascular Diseases Vasodilation Western World atherogenesis cell motility cytokine femoral artery in vivo inhibitor/antagonist injured macrophage mouse model novel progenitor promoter receptor research study response response to injury restenosis sex therapeutic target tool vascular smooth muscle cell proliferation

项目摘要

ABSTRACT Adenosine binding to adenylyl cyclase stimulatory (A2-type) adenosine receptors (ARs) induces coronary vasodilatation, inhibits human aortic vascular smooth muscle cell proliferation, and affects arterial wall matrix production, all of which are important components of atherosclerosis/restenosis. The role of the low affinity A2bARs in regulating vascular pathology in vivo had not been examined prior to our study. To further address this, we generated the first A2bAR-knockout (KO)/reporter gene-knock-in mouse model and showed reported gene expression primarily in VSMC and macrophages, in accordance with the endogenous profile in control mice. Augmentation of proinflammatory cytokines, such as tumor necrosis factor-¿ (TNF-¿), is the underlying mechanism for an observed upregulation of leukocyte adhesion in the vasculature of these A2bAR KO mice, as compared with age-, sex-, and strain-matched control mice. On the other hand, the A2bAR gene receptor, itself, is induced by TNF-¿, suggesting a regulatory loop. A2bAR KO mice display greater lesion formation after guidewire-induced femoral artery injury. This occurs in association with the upregulation of CXCR4, a protein known to promote mobilization of progenitors and inflammatory cells to the vessel by interaction with its ligand stromal cell-derived factor-1 (SDF-1). Furthermore, bone marrow (BM) transplantation experiments indicate that the inflammatory response and vascular lesion formation are significantly regulated by BM-derived A2bARs. Building upon these novel findings, we hypothesize that A2bAR-mediated signaling regulates the expression of CXRC4 and, hence, plays a vital role in vascular lesion formation. It is our contention that macrophage A2bARs, via their ability to control the level of inflammatory cytokines, are capable of significantly protecting against vascular pathology on their own, consistent with the BM transplantation experiments. Finally, identifying mechanisms of A2bAR gene regulation by TNF-¿ should lead the way for the development of strategies for controlling vascular dysfunction during inflammation. Three specific aims of research are proposed: Aim 1. To examine the direct participation of BM cells and/or their signals in mediating effects of the A2bAR on lesion formation during vascular injury and atherosclerosis, and to study related mechanisms, with a focus on the contribution of macrophage A2bARs. Aim 2. To elucidate the mechanism of control of the CXCR4/SDF-1 axis by the A2bAR. Aim 3. To study the mechanism of A2bAR gene activation by TNF-¿ in primary cultures and in vivo. Taken together, our proposed investigations should shed new light on the role of A2bARs in the pathogenesis of vascular dysfunction, and could focus attention on A2bAR activation as a therapeutic target.

抽象的腺苷与腺苷环酶模拟（A2型）腺苷受体（ARS）结合可诱导冠状动脉血管舒张，抑制人主动脉血管平滑肌细胞增殖，并影响动脉壁基质生产，所有这些都是动脉粥样硬化/再狭窄的重要组成部分。低亲和力的作用在我们的研究之前，尚未对体内调节血管病理的A2bars进行检查。进一步解决这，我们生成了第一个A2BAR-KNOCKOUT（KO）/报告基因基因敲入鼠标模型根据对照中的内源性轮廓，VSMC和巨噬细胞中的基因表达初级老鼠。促炎细胞因子的增强，例如肿瘤坏死因子 - （TNF-¿），是基础在这些A2BAR KO小鼠的脉管系统中观察到白细胞粘合剂上调的机制，与年龄，性别和菌株匹配的对照小鼠相比。另一方面，A2bar基因受体，本身是由TNF-€诱导的，暗示了调节循环。 A2BAR KO小鼠显示出更大的病变形成指南引起的股动脉损伤。这与蛋白质CXCR4的上调有关已知可以通过与配体相互作用来促进祖细胞和炎症细胞向血管动员基质细胞衍生的因子1（SDF-1）。此外，骨髓（BM）移植实验表明炎症反应和血管病变形成受BM衍生 A2bars。在这些新颖的发现的基础上，我们假设A2BAR介导的信号传导调节 CXRC4的表达以及因此在血管病变形成中起着至关重要的作用。我们的论点是巨噬细胞A2BAR通过控制炎症细胞因子水平的能力，能够显着与BM移植实验相一致，以保护自己的血管病理。最后，通过TNF- - 识别A2BAR基因调节的机制应为发展带来发展炎症期间控制血管功能障碍的策略。研究的三个具体目标是提议：目的1。检查BM细胞的直接参与和/或它们的信号在中介作用中在血管损伤和动脉粥样硬化期间病变形成的A2BAR，并研究相关机制专注于巨噬细胞A2bars的贡献。目标2。阐明控制机制 A2BAR的CXCR4/SDF-1轴。目的3。研究TNF-在原始文化和体内。综上所述，我们拟议的调查应该对血管功能障碍发病机理中的A2BAR，可以将注意力集中在A2BAR激活上治疗靶标。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Actinin-1 binds to the C-terminus of A2B adenosine receptor (A2BAR) and enhances A2BAR cell-surface expression.

Actinin-1 与 A2B 腺苷受体 (A2BAR) 的 C 末端结合并增强 A2BAR 细胞表面表达。

DOI：
10.1042/bcj20160272
发表时间：
2016
期刊：
The Biochemical journal
影响因子：
0
作者：
Sun,Ying;Hu,Wenbao;Yu,Xiaojie;Liu,Zhengzhao;Tarran,Robert;Ravid,Katya;Huang,Pingbo
通讯作者：
Huang,Pingbo

Vascular smooth muscle cell polyploidy: An adaptive or maladaptive response?