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.

摘要

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