The role of adenosine kinase in atherosclerosis

描述（由申请人提供）：动脉粥样硬化是一种动脉血管壁的慢性炎症性疾病，从脂肪条纹发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的相互作用，单核细胞募集到动脉血管壁，并随后转化为富含脂质的泡沫细胞，引发和维持动脉粥样硬化。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。该建议的中心假设是抑制腺苷激酶（ADK）抑制动脉粥样硬化的炎症方面，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，作用于炎症部位，在调节炎症反应中起核心作用。然而，腺苷或腺苷类似物的短半衰期和全身副作用限制了它们的应用。ADK是催化腺苷磷酸化为AMP的细胞内酶。ADK的抑制增加了细胞内隔室中腺苷的水平，并导致细胞外隔室中随后的增加。ADK抑制在动物模型中有效抑制许多炎性疾病。然而，ADK抑制在动脉粥样硬化中的作用尚未确定。我们最近发现：（i）ADK抑制剂抑制小鼠动脉粥样硬化病变的形成;（ii）内皮细胞中ADK敲低降低了精氨酸诱导的内皮活化;和（iii）髓样白细胞中ADK的缺乏减少了小鼠动脉粥样硬化病变的形成。本项目的目的是使用组织特异性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缺乏对动脉内皮炎性反应减少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缺乏对单核细胞向动脉粥样硬化动脉募集的下降、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PI 3 K/Akt和腺苷受体2A（A2 AR）对ADK缺乏的影响的贡献。这些研究将对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剂的使用具有重要意义。

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.