Adenosine Receptors and Atherogenesis

腺苷受体和动脉粥样硬化形成

• 批准号: 7789620
• 负责人: KATYA RAVID
• 金额: $ 40.63万
• 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 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7789620
• 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; Hand; 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; Tumor Necrosis Factors; Up-Regulation; Vascular Diseases; Vasodilation; Western World; atherogenesis; cell motility; cytokine; femoral artery; in vivo; inhibitor/antagonist; injured; macrophage; mouse model; novel; progenitor; promoter; public health relevance; receptor; research study; response; response to injury; restenosis; sex; therapeutic target; tool; vascular smooth muscle cell proliferation

DESCRIPTION (provided by applicant): 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-1 (TNF-1), 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-1, 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-1 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-1 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. PUBLIC HEALTH RELEVANCE: Atherosclerosis is a leading cause of vascular disease in the Western world. Our research proposal builds upon novel findings, including the identification of the A2b adenosine receptor as protective against atherosclerosis/restenosis. The mechanisms leading to this protection and the control of expression of this receptor gene are the focus of research in this proposal.

描述（由申请人提供）：腺苷结合腺苷酸环化酶刺激（a2型）腺苷受体（ARs）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，影响动脉壁基质的产生，这些都是动脉粥样硬化/再狭窄的重要组成部分。在我们的研究之前，还没有研究过低亲和力A2bARs在体内调节血管病理中的作用。为了进一步解决这一问题，我们建立了第一个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，与对照小鼠的内源性谱一致。与年龄、性别和菌株匹配的对照组小鼠相比，促炎细胞因子，如肿瘤坏死因子-1 （TNF-1）的增强，是这些A2bAR KO小鼠血管中白细胞粘附上调的潜在机制。另一方面，A2bAR基因受体本身是由TNF-1诱导的，这表明存在一个调节回路。A2bAR KO小鼠在导丝诱导的股动脉损伤后表现出更大的病变形成。这与CXCR4的上调有关，CXCR4是一种已知的蛋白质，通过与其配体基质细胞衍生因子-1 （SDF-1）的相互作用，促进祖细胞和炎症细胞向血管的动员。此外，骨髓移植实验表明，炎症反应和血管病变形成受骨髓源性A2bARs的显著调节。基于这些新发现，我们假设a2bar介导的信号调节CXRC4的表达，因此在血管病变形成中起着至关重要的作用。我们认为，巨噬细胞A2bARs通过其控制炎症细胞因子水平的能力，能够显著地保护自身免受血管病理学的影响，这与BM移植实验一致。最后，确定TNF-1调控A2bAR基因的机制，将为炎症期间控制血管功能障碍的策略的制定提供指导。提出了三个具体的研究目标：目标1。探讨BM细胞和/或其信号直接参与A2bAR介导血管损伤和动脉粥样硬化过程中病变形成的作用，并研究相关机制，重点关注巨噬细胞A2bAR的作用。目标2。目的：阐明A2bAR对CXCR4/SDF-1轴的调控机制。目标3。目的：研究TNF-1在原代培养和体内活化A2bAR基因的机制。综上所述，我们提出的研究将揭示A2bAR在血管功能障碍发病机制中的作用，并将注意力集中在A2bAR激活作为治疗靶点上。公共卫生相关性：动脉粥样硬化是西方世界血管疾病的主要原因。我们的研究计划建立在新发现的基础上，包括A2b腺苷受体对动脉粥样硬化/再狭窄的保护作用。导致这种保护的机制和该受体基因的表达控制是本提案的研究重点。