P2Y6 Deficiency Limits Vascular Inflammation and Atherosclerosis in Mice
P2Y6 Deficiency Limits Vascular Inflammation and Atherosclerosis in Mice
复制标题
DOI：
10.1161/atvbaha.114.303585
复制
发表时间：
2014-10
期刊：
影响因子：
--
通讯作者：
P. Stachon;A. Peikert;N. Michel;S. Hergeth;T. Marchini;D. Wolf;B. Dufner;N. Hoppe;C. K. Ayata;M. Grimm;S. Cicko;Lisa Schulte;J. Reinöhl;C. von zur Muhlen;C. Bode;M. Idzko;A. Zirlik
中科院分区：
文献类型：
--
作者：
P. Stachon;A. Peikert;N. Michel;S. Hergeth;T. Marchini;D. Wolf;B. Dufner;N. Hoppe;C. K. Ayata;M. Grimm;S. Cicko;Lisa Schulte;J. Reinöhl;C. von zur Muhlen;C. Bode;M. Idzko;A. Zirlik
目的：ATP、ADP、UTP和UDP等核苷酸在激活或死亡的细胞释放到细胞外间隙时，通过嘌呤能受体作为促炎危险信号。UDP通过诱导趋化因子如单核细胞趋化蛋白1、白介素8或其小鼠同源物CCL1(趋化因子[C-C基序]配体1)/角质形成细胞趋化因子、CXCL2(趋化因子[C-X-C基序]配体2)/巨噬细胞炎症蛋白2、CXCL5(趋化因子[C-X-C基序]配体5)/lix以及黏附分子如血管细胞黏附分子1和细胞间黏附分子1等黏附分子的表达，与嘌呤能受体Y6(P2Y6)结合并促进血管炎症。由于动脉粥样硬化是一种慢性炎症性疾病，由白细胞聚集到血管壁上驱动，我们假设P2Y6在动脉粥样硬化形成中起到了作用。方法和结果--通过活体显微镜评估，用UDP对野生型小鼠进行腹膜内刺激，可诱导白细胞卷曲并黏附于血管壁。这种效应在P2Y6基因缺陷的小鼠中不存在。动脉粥样硬化低密度脂蛋白受体缺陷小鼠摄入高胆固醇饮食16周后，其动脉中P2Y6的转录和蛋白表达显著高于各自的对照组。最后，与P2Y6+/+/低密度脂蛋白受体缺陷小鼠相比，摄入高胆固醇饮食16周的P2Y6−/−/低密度脂蛋白受体缺陷小鼠的动脉粥样硬化病变明显较小。骨髓移植证实了P2Y6在血管驻留细胞上的关键作用，很可能是内皮细胞，在白细胞募集和动脉粥样硬化形成中起着关键作用。免疫组织化学检测显示，P2Y6基因缺陷小鼠的动脉粥样硬化病变含有较少的巨噬细胞和较少的脂类。从机制上讲，血管细胞黏附分子1和白介素6的RNA表达在这些皮损中降低，P2Y6缺陷的巨噬细胞摄取较少修饰的低密度脂蛋白胆固醇。结论--我们首次发现，P2Y6缺乏限制了小鼠的动脉粥样硬化和斑块炎症。
Objective— Nucleotides such as ATP, ADP, UTP, and UDP serve as proinflammatory danger signals via purinergic receptors on their release to the extracellular space by activated or dying cells. UDP binds to the purinergic receptor Y6 (P2Y6) and propagates vascular inflammation by inducing the expression of chemokines such as monocyte chemoattractant protein 1, interleukin-8, or its mouse homologsCCL1 (chemokine [C-C motif] ligand 1)/keratinocyte chemokine, CXCL2 (chemokine [C-X-C motif] ligand 2)/macrophage inflammatory protein 2, and CXCL5 (chemokine [C-X-C motif] ligand 5)/LIX, and adhesion molecules such as vascular cell adhesion molecule 1 and intercellular cell adhesion molecule 1. Thus, P2Y6 contributes to leukocyte recruitment and inflammation in conditions such as allergic asthma or sepsis. Because atherosclerosis is a chronic inflammatory disease driven by leukocyte recruitment to the vessel wall, we hypothesized a role of P2Y6 in atherogenesis. Approach and Results— Intraperitoneal stimulation of wild-type mice with UDP induced rolling and adhesion of leukocytes to the vessel wall as assessed by intravital microscopy. This effect was not present in P2Y6-deficient mice. Atherosclerotic aortas of low-density lipoprotein receptor–deficient mice consuming high-cholesterol diet for 16 weeks expressed significantly more transcripts and protein of P2Y6 than respective controls. Finally, P2Y6 −/−/low-density lipoprotein receptor–deficient mice consuming high-cholesterol diet for 16 weeks developed significantly smaller atherosclerotic lesions compared with P2Y6 +/+/low-density lipoprotein receptor–deficient mice. Bone marrow transplantation identified a crucial role of P2Y6 on vascular resident cells, most likely endothelial cells, on leukocyte recruitment and atherogenesis. Atherosclerotic lesions of P2Y6-deficient mice contained fewer macrophages and fewer lipids as determined by immunohistochemistry. Mechanistically, RNA expression of vascular cell adhesion molecule 1 and interleukin-6 was decreased in these lesions and P2Y6-deficient macrophages took up less modified low-density lipoprotein cholesterol. Conclusions— We show for the first time that P2Y6 deficiency limits atherosclerosis and plaque inflammation in mice.