The role of adenosine kinase in atherosclerosis

腺苷激酶在动脉粥样硬化中的作用

• 批准号: 8583339
• 负责人: YUQING HUO
• 金额: $ 37.08万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-08 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8583339
• 关键词: Adenosine; Adenosine Kinase; Adhesiveness; Adverse effects; Affect; Animal Model; Animals; Apolipoprotein E; Arterial Fatty Streak; Arteries; Atherosclerosis; Binding; Biological Assay; Blood Vessels; Bone Marrow Cells; CD36 gene; Cell Adhesion Molecules; Cells; Chronic; Development; Diet; Disease; Down-Regulation; Endothelial Cells; Endothelium; Enzymes; Foam Cells; Genetic; Goals; Growth; Half-Life; Homing; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Lesion; Leukocytes; Ligands; Lipids; Macrophage Activation; Messenger RNA; Mus; Myelogenous; Myeloid Cells; Pathway interactions; Phosphorylation; Physiology; Play; Prevention; Process; Production; Proteins; Purine Nucleosides; Purinergic P1 Receptors; Regulation; Research Project Grants; Role; Signal Transduction; Site; Testing; Therapeutic Agents; Tissues; Transplantation; analog; base; chemokine; chemokine receptor; cytokine; design; evidence base; extracellular; feeding; in vitro Assay; inhibitor/antagonist; kinase inhibitor; macrophage; migration; monocyte; neovascularization; novel; novel strategies; prevent; research study; response; uptake; vasa vasorum

DESCRIPTION (provided by applicant): Atherosclerosis is a chronic inflammatory disease of the arterial vessel wall that progresses from a fatty streak to a fibrofattymatrix and fibrous plaque. Monocyte interactions with the inflamed endothelium, monocyte recruitment to the arterial vesselwall and their subsequent transformation to lipid-enriched foam cells initiate and sustain atherosclerosis. The long-term goal of this research project is to elucidate the mechanisms underlying the regulation of the inflammatory aspects of atherosclerosis so that novel evidence-based approaches can be developed to treat atherosclerosis. The central hypothesis of this proposal is that suppressing adenosine kinase (ADK) inhibits the inflammatory aspects of atherosclerosis and further curbs the formation of atherosclerotic lesions. Adenosine, a purine nucleoside that is elaborated the sites of inflammation, has a central role in regulating the inflammatory response. However, the short half-life and systemic side effects of adenosine or adenosine analogues limit their application. ADK is an intracellular enzyme that catalyzes the phosphorylation of adenosine to AMP. Inhibition of ADK increases the levels of adenosine in the intracellular compartment and causes a subsequent increase in the extracellular compartment. ADK inhibition is efficacious at suppressing many inflammatory diseases in animal models. However, the role of ADK inhibition in atherosclerosis has not been defined. We have recently found the following: (i) an ADK inhibitor suppresses the formation of atherosclerotic lesions in mice; (ii) ADK knockdown in endothelial cells decreases cytokine-induced endothelial activation; and (iii) the deficiency of ADK in myeloid leukocytes reduces the formation of atherosclerotic lesions in mice. The goal of this project is to use tissue- specific ADK-deficient mice to investigate the extent to which ADK deficiency in endothelial cells or monocytes/macrophages contributes to the reduction of inflammatory responses and the suppression of atherosclerosis. In specific aim 1, we will investigate the effect of endothelial ADK deficiency on the decreased inflammatory adhesiveness of the arterial endothelium and the suppressed formation of atherosclerotic lesions. In specific aims 2 to 4, we will investigate the effects of monocyte ADK deficiency on the decline of monocyte recruitment to atherosclerotic arteries, macrophage activation and foam cell formation, as well as the growth of advanced atherosclerotic lesions. We will also determine the contribution of the PI3K/Akt and adenosine receptor 2A (A2AR) to the effects of ADK deficiency. These studies will have significant implications for the use of ADK inhibitors as therapeutic agents to prevent and treat atherosclerosis and its complications.

描述（由申请人提供）：动脉粥样硬化是动脉血管壁的一种慢性炎症性疾病，从脂肪条纹进展为纤维脂肪基质和纤维斑块。单核细胞与发炎的内皮细胞相互作用、单核细胞募集到动脉血管壁以及随后转化为富含脂质的泡沫细胞，引发并维持动脉粥样硬化。该研究项目的长期目标是阐明动脉粥样硬化炎症方面的调节机制，以便开发新的循证方法来治疗动脉粥样硬化。该提议的中心假设是抑制腺苷激酶（ADK）可以抑制动脉粥样硬化的炎症，并进一步抑制动脉粥样硬化病变的形成。腺苷是一种嘌呤核苷，在炎症部位发挥作用，在调节炎症反应中发挥着核心作用。然而，腺苷或腺苷类似物的半衰期短和全身副作用限制了它们的应用。 ADK 是一种细胞内酶，催化腺苷磷酸化为 AMP。 ADK 的抑制会增加细胞内区室中的腺苷水平，并导致细胞外区室中的腺苷水平随后增加。 ADK 抑制可有效抑制动物模型中的许多炎症性疾病。然而，ADK 抑制在动脉粥样硬化中的作用尚未明确。我们最近发现：(i) ADK 抑制剂可抑制小鼠动脉粥样硬化病变的形成； (ii) 内皮细胞中 ADK 敲低可降低细胞因子诱导的内皮激活； (iii) 骨髓白细胞中 ADK 的缺乏减少了小鼠动脉粥样硬化病变的形成。该项目的目标是使用组织特异性 ADK 缺陷小鼠来研究内皮细胞或单核细胞/巨噬细胞中 ADK 缺陷在多大程度上有助于减少炎症反应和抑制动脉粥样硬化。在具体目标1中，我们将研究内皮ADK缺乏对动脉内皮炎症粘附力降低和动脉粥样硬化病变形成抑制的影响。在具体目标 2 至 4 中，我们将研究单核细胞 ADK 缺乏对动脉粥样硬化动脉单核细胞募集下降、巨噬细胞活化和泡沫细胞形成以及晚期动脉粥样硬化病变生长的影响。我们还将确定 PI3K/Akt 和腺苷受体 2A (A2AR) 对 ADK 缺陷影响的贡献。这些研究对于使用 ADK 抑制剂作为预防和治疗动脉粥样硬化及其并发症的治疗药物具有重要意义。