Adenosine Receptors and Atherogenesis

腺苷受体和动脉粥样硬化形成

• 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
• 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

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 腺苷与腺苷酸环化酶刺激性（A2 型）腺苷受体 (AR) 结合可诱导冠状动脉 舒张血管，抑制人主动脉血管平滑肌细胞增殖，影响动脉壁基质 产生，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，尚未检查 A2bAR 在体内调节血管病理学的作用。为进一步解决 为此，我们生成了第一个 A2bAR 敲除 (KO)/报告基因敲入小鼠模型，并显示了报道的 基因表达主要在 VSMC 和巨噬细胞中，与对照中的内源性谱一致 老鼠。促炎细胞因子的增加，例如肿瘤坏死因子-¿ (TNF-¿)，是潜在的 在这些 A2bAR KO 小鼠的脉管系统中观察到白细胞粘附上调的机制， 与年龄、性别和品系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，表明存在调节环。 A2bAR KO 小鼠在 导丝引起的股动脉损伤。这与 CXCR4（一种蛋白质）的上调有关。 已知通过与其配体相互作用促进祖细胞和炎症细胞向血管的动员 基质细胞衍生因子-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到 BM 来源的显着调节 A2bAR。基于这些新发现，我们假设 A2bAR 介导的信号传导调节 CXRC4 的表达，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 通过其控制炎症细胞因子水平的能力，能够显着 其自身可防止血管病变，与 BM 移植实验一致。最后， 确定 TNF-¿ 调节 A2bAR 基因的机制应该为开发 控制炎症期间血管功能障碍的策略。研究的三个具体目标是 建议： 目标 1. 检验 BM 细胞和/或其信号在细胞因子介导作用中的直接参与 A2bAR对血管损伤和动脉粥样硬化过程中病变形成的影响，并研究相关机制， 重点关注巨噬细胞 A2bAR 的贡献。目标 2. 阐明控制机制 CXCR4/SDF-1 轴由 A2bAR 控制。目的3.研究TNF-¿激活A2bAR基因的机制 原代培养和体内。总而言之，我们提议的调查应该为我们的作用提供新的启示。 A2bAR 在血管功能障碍的发病机制中，并且可以将注意力集中在 A2bAR 激活作为 治疗目标。

项目成果

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
• 作者: Sun,Ying;Hu,Wenbao;Yu,Xiaojie;Liu,Zhengzhao;Tarran,Robert;Ravid,Katya;Huang,Pingbo
• 通讯作者: Huang,Pingbo