Knockout mice reveal a role for P2Y6 receptor in macrophages, endothelial cells, and vascular smooth muscle cells
Knockout mice reveal a role for P2Y6 receptor in macrophages, endothelial cells, and vascular smooth muscle cells
复制标题
DOI：
10.1124/mol.108.046904
复制
发表时间：
2008-09-01
影响因子：
3.6
通讯作者：
Robaye, Bernard
中科院分区：
文献类型：
--
作者：
Bar, Isabelle;Guns, Pieter-Jan;Robaye, Bernard
P2Y 受体是由细胞外核苷酸激活的 G 蛋白偶联受体。 P2Y(6)受体被UDP选择性激活，其转录本已在许多器官中检测到，包括脾、胸腺、肠、白细胞和主动脉。为了研究该受体的生物学功能，我们通过基因靶向产生了 P2Y(6) 缺失小鼠。 P2Y(6) 敲除 (KO) 小鼠具有存活能力，并且在生长或生育力方面与野生型 (WT) 小鼠没有区别。在巯基乙酸引发的巨噬细胞中，响应 UDP 刺激而产生的磷酸肌醇的产生消失，表明 P2Y(6) 是小鼠巨噬细胞表达的独特的 UDP 响应受体。此外，在UDP存在的情况下，响应脂多糖刺激而释放的白细胞介素6和巨噬细胞炎症蛋白2（但不是肿瘤坏死因子-α）的量显着增加，并且这种作用在P2Y（6）KO巨噬细胞中消失。在 KO P2Y(6) 小鼠中，UDP 引起的主动脉内皮依赖性松弛被消除。当内皮一氧化氮合酶被阻断时观察到的UDP对主动脉的收缩作用在P2Y(6)缺失小鼠中也被消除。总之，我们培育了 P2Y(6) 缺陷型小鼠，并表明这些小鼠的巨噬细胞、内皮细胞和血管平滑肌细胞对 UDP 的反应有缺陷。这些观察结果可能与多种病理生理学状况有关，例如动脉粥样硬化或高血压。
P2Y receptors are G-protein-coupled receptors activated by extracellular nucleotides. The P2Y(6) receptor is selectively activated by UDP, and its transcript has been detected in numerous organs, including the spleen, thymus, intestine, blood leukocytes, and aorta. To investigate the biological functions of this receptor, we generated P2Y(6)-null mice by gene targeting. The P2Y(6) knockout (KO) mice are viable and are not distinguishable from the wild-type (WT) mice in terms of growth or fertility. In thioglycollate-elicited macrophages, the production of inositol phosphate in response to UDP stimulation was lost, indicating that P2Y(6) is the unique UDP-responsive receptor expressed by mouse macrophages. Furthermore, the amount of interleukin-6 and macrophage-inflammatory protein-2, but not tumor necrosis factor-alpha, released in response to lipopolysaccharide stimulation was significantly enhanced in the presence of UDP, and this effect was lost in the P2Y(6) KO macrophages. The endothelium-dependent relaxation of the aorta by UDP was abolished in KO P2Y(6) mice. The contractile effect of UDP on the aorta, observed when endothelial nitric-oxide synthase is blocked, was also abolished in P2Y(6)-null mice. In conclusion, we generated P2Y(6)-deficient mice and have shown that these mice have a defective response to UDP in macrophages, endothelial cells, and vascular smooth muscle cells. These observations might be relevant to several physiopathological conditions such as atherosclerosis or hypertension.