细胞外ATP通过嘌呤能受体Y2诱导小鼠血管炎症和动脉粥样硬化。
Extracellular ATP Induces Vascular Inflammation and Atherosclerosis via Purinergic Receptor Y2 in Mice.
作者信息
Stachon Peter, Geis Serjosha, Peikert Alexander, Heidenreich Adrian, Michel Nathaly Anto, Ünal Fatih, Hoppe Natalie, Dufner Bianca, Schulte Lisa, Marchini Timoteo, Cicko Sanja, Ayata Korcan, Zech Andreas, Wolf Dennis, Hilgendorf Ingo, Willecke Florian, Reinöhl Jochen, von Zur Mühlen Constantin, Bode Christoph, Idzko Marco, Zirlik Andreas
机构信息
From the Atherogenesis Research Group, University Heart Center Freiburg, Department of Cardiology and Angiology I (P.S., S.G., A.P., A.H., N.A.M., F.Ü., N.H., B.D., L.S., T.M., D.W., I.H., F.W., J.R., C.v.z.M., C.B., A.Z.) and Department of Pneumology (S.C., K.A., A.Z., M.I.), University of Freiburg, Freiburg, Germany.
出版信息
Arterioscler Thromb Vasc Biol. 2016 Aug;36(8):1577-86. doi: 10.1161/ATVBAHA.115.307397. Epub 2016 Jun 23.
OBJECTIVE
A solid body of evidence supports a role of extracellular ATP and its P2 receptors in innate and adaptive immunity. It promotes inflammation as a danger signal in various chronic inflammatory diseases. Thus, we hypothesize contribution of extracellular ATP and its receptor P2Y2 in vascular inflammation and atherosclerosis.
APPROACH AND RESULTS
Extracellular ATP induced leukocyte rolling, adhesion, and migration in vivo as assessed by intravital microscopy and in sterile peritonitis. To test the role of extracellular ATP in atherosclerosis, ATP or saline as control was injected intraperitoneally 3× a week in low-density lipoprotein receptor(-/-) mice consuming high cholesterol diet. Atherosclerosis significantly increased after 16 weeks in ATP-treated mice (n=13; control group, 0.26 mm2; ATP group, 0.33 mm2; P=0.01). To gain into the role of ATP-receptor P2Y2 in ATP-induced leukocyte recruitment, ATP was administered systemically in P2Y2-deficient or P2Y2-competent mice. In P2Y2-deficient mice, the ATP-induced leukocyte adhesion was significantly reduced as assessed by intravital microscopy. P2Y2 expression in atherosclerosis was measured by real-time polymerase chain reaction and immunohistochemistry and demonstrates an increased expression mainly caused by influx of P2Y2-expressing macrophages. To investigate the functional role of P2Y2 in atherogenesis, P2Y2-deficient low-density lipoprotein receptor(-/-) mice consumed high cholesterol diet. After 16 weeks, P2Y2-deficient mice showed significantly reduced atherosclerotic lesions with decreased macrophages compared with P2Y2-competent mice (n=11; aortic arch: control group, 0.25 mm(2); P2Y2-deficient, 0.14 mm2; P=0.04). Mechanistically, atherosclerotic lesions from P2Y2-deficient mice expressed less vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 RNA.
CONCLUSIONS
We show that extracellular ATP induces vascular inflammation and atherosclerosis via activation of P2Y2.
目的
大量证据支持细胞外ATP及其P2受体在先天性和适应性免疫中发挥作用。它作为一种危险信号在各种慢性炎症性疾病中促进炎症反应。因此，我们推测细胞外ATP及其受体P2Y2在血管炎症和动脉粥样硬化中起作用。
方法与结果
通过活体显微镜检查和无菌性腹膜炎评估，细胞外ATP在体内诱导白细胞滚动、黏附和迁移。为了测试细胞外ATP在动脉粥样硬化中的作用，在食用高胆固醇饮食的低密度脂蛋白受体缺失（-/-）小鼠中，每周腹腔注射3次ATP或作为对照的生理盐水。16周后，ATP处理的小鼠动脉粥样硬化显著增加（n = 13；对照组，0.26平方毫米；ATP组，0.33平方毫米；P = 0.01）。为了深入了解ATP受体P2Y2在ATP诱导的白细胞募集中的作用，在P2Y2缺陷或P2Y2正常的小鼠中全身给予ATP。通过活体显微镜检查评估发现，在P2Y2缺陷小鼠中，ATP诱导的白细胞黏附显著减少。通过实时聚合酶链反应和免疫组织化学测量动脉粥样硬化中P2Y2的表达，结果显示其表达增加，主要是由表达P2Y2的巨噬细胞流入所致。为了研究P2Y2在动脉粥样硬化发生中的功能作用，让P2Y2缺陷的低密度脂蛋白受体缺失（-/-）小鼠食用高胆固醇饮食。16周后，与P2Y2正常的小鼠相比，P2Y2缺陷小鼠的动脉粥样硬化病变显著减少且巨噬细胞数量减少（n = 11；主动脉弓：对照组，0.25平方毫米；P2Y2缺陷组，0.14平方毫米；P = 0.04）。从机制上讲，P2Y2缺陷小鼠的动脉粥样硬化病变中血管细胞黏附分子-1和细胞间黏附分子-1的RNA表达较少。
结论
我们表明细胞外ATP通过激活P2Y2诱导血管炎症和动脉粥样硬化。
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