Inactivation of the adenosine A2A receptor protects apolipoprotein E-deficient mice from atherosclerosis.
Inactivation of the adenosine A2A receptor protects apolipoprotein E-deficient mice from atherosclerosis.
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DOI：
10.1161/atvbaha.109.188839
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发表时间：
2009-07
期刊：
影响因子：
--
通讯作者：
Huo Y
中科院分区：
文献类型：
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作者：
Wang H;Zhang W;Zhu C;Bucher C;Blazar BR;Zhang C;Chen JF;Linden J;Wu C;Huo Y
动脉粥样硬化是一种动脉血管壁的慢性炎症性疾病。A2 A受体（A2 AR）在腺苷的许多抗炎作用中起着核心作用。然而，A2 AR在动脉粥样硬化中的作用尚不清楚。敲除载脂蛋白E缺陷（Apoe−/−/A2 AR −/−）小鼠中的A2 AR导致体重和血液胆固醇和促炎细胞因子水平增加，以及动脉粥样硬化病变的炎症状态。出乎意料的是，Apoe−/−/A2 AR −/−小鼠出现了较小的病变，就像骨髓来源细胞（BMDC）中缺乏A2 AR的嵌合Apoe−/−小鼠一样。这些小鼠的病变表现出低密度的泡沫细胞，A2 AR缺陷型单核细胞的归巢能力没有改变。在Apoe−/−/A2 AR −/−小鼠的动脉粥样硬化病变中检测到泡沫细胞凋亡增加。在A2 AR的情况下，与氧化LDL或体内形成的泡沫细胞孵育的巨噬细胞也表现出增加的凋亡。泡沫细胞中A2 AR缺乏导致p38有丝分裂原活化蛋白激酶（MAPK）活性增加。抑制p38磷酸化消除了A2 AR缺陷泡沫细胞的凋亡增加。A2 AR的失活，特别是在BMDCs中，抑制动脉粥样硬化病变的形成，表明A2 AR失活可能对动脉粥样硬化的治疗有用。
Atherosclerosis is a chronic inflammatory disease of the arterial vessel wall. The A2A receptor (A2AR) plays a central role in many anti-inflammatory effects of adenosine. However, the role of A2AR in atherosclerosis is not clear. The knockout of A2AR in apolipoprotein E–deficient (Apoe−/−/A2AR−/−) mice led to an increase in body weight and levels of blood cholesterol and proinflammatory cytokines, as well as the inflammation status of atherosclerotic lesions. Unexpectedly, Apoe−/−/A2AR−/− mice developed smaller lesions, as did chimeric Apoe−/− mice lacking A2AR in bone-marrow-derived cells (BMDCs). The lesions of those mice exhibited a low density of foam cells and the homing ability of A2AR-deficient monocytes did not change. Increased foam cell apoptosis was detected in atherosclerotic lesions of Apoe−/−/A2AR−/− mice. In the absence of A2AR, macrophages incubated with oxidized LDL or in vivo-formed foam cells also exhibited increased apoptosis. A2AR deficiency in foam cells resulted in an increase in p38 mitogen-activated protein kinase (MAPK) activity. Inhibition of p38 phosphorylation abrogated the increased apoptosis of A2AR-deficient foam cells. Inactivation of A2AR, especially in BMDCs, inhibits the formation of atherosclerotic leisons, suggesting that A2AR inactivation may be useful for the treatment of atherosclerosis.