P2Y receptors and atherosclerosis in apolipoprotein E-deficient mice
P2Y receptors and atherosclerosis in apolipoprotein E-deficient mice
复制标题
DOI：
10.1111/j.1476-5381.2009.00497.x
复制
发表时间：
2010-01-01
影响因子：
7.3
通讯作者：
Bult, Hidde
中科院分区：
文献类型：
--
作者：
Guns, Pieter-Jan D. F.;Hendrickx, Jan;Bult, Hidde
背景和目的：P2Y核苷酸受体参与调节血管张力、平滑肌细胞(SMC)增殖和炎症反应。本研究旨在探讨它们是否参与动脉粥样硬化的形成。实验方法：用RT-PCR方法对载脂蛋白E基因缺陷(apoE(-/-))小鼠动脉粥样硬化和无斑块的主动脉组织中P2Y受体的mRNA进行定量。在J774巨噬细胞中检测巨噬细胞的活化，并在胆固醇喂养的apoE(-/-)小鼠中评价非选择性嘌呤受体拮抗剂对动脉粥样硬化的影响。P2Y(1)或P2Y(4)受体mRNA表达低或检测不到，且不受动脉粥样硬化的影响。培养的J774巨噬细胞的P2Y(6)基因表达水平高于培养的主动脉平滑肌细胞。此外，斑块的免疫组织化学染色显示P2Y(6)阳性的巨噬细胞，但很少的SMC，提示巨噬细胞募集是动脉粥样硬化过程中P2Y(6)受体mRNA增加的原因。与三磷酸腺苷相反，P_2Y(6)选择性激动剂UDP可增加J774巨噬细胞诱导型一氧化氮合酶和白介素6的表达和活性，这种作用可被苏拉明(100-300mM)或pyridoxal-phosphate-6-azophenyl-2‘-4’-disulphonic酸(10-30mM)所阻断。最后，用苏拉明或PPADS(分别为50和25 mg·kg(-1)·day(-1))治疗胆固醇喂养的apoE(-/-)小鼠4周后，可缩小斑块大小，但不改变斑块成分(相对SMC和巨噬细胞含量)或细胞复制。结论和暗示：这些结果提示核苷酸受体，特别是P2Y(6)受体参与动脉粥样硬化，并值得进一步研究选择性紫色受体拮抗剂或P2Y(6)受体缺陷小鼠。《英国药理学杂志》(2010年)159326-336；DOI：10.1111/j.1476-5381.2009.00497.x；2009年12月24日在线发布
Background and purpose: P2Y nucleotide receptors are involved in the regulation of vascular tone, smooth muscle cell (SMC) proliferation and inflammatory responses. The present study investigated whether they are involved in atherosclerosis.Experimental approach: mRNA of P2Y receptors was quantified (RT-PCR) in atherosclerotic and plaque-free aorta segments of apolipoprotein E-deficient (apoE(-/-)) mice. Macrophage activation was assessed in J774 macrophages, and effects of non-selective purinoceptor antagonists on atherosclerosis were evaluated in cholesterol-fed apoE(-/-) mice.Key results: P2Y(6) receptor mRNA was consistently elevated in segments with atherosclerosis, whereas P2Y(2) receptor expression remained unchanged. Expression of P2Y(1) or P2Y(4) receptor mRNA was low or undetectable, and not influenced by atherosclerosis. P2Y(6) mRNA expression was higher in cultured J774 macrophages than in cultured aortic SMCs. Furthermore, immunohistochemical staining of plaques demonstrated P2Y(6)-positive macrophages, but few SMCs, suggesting that macrophage recruitment accounted for the increase in P2Y(6) receptor mRNA during atherosclerosis. In contrast to ATP, the P2Y(6)-selective agonist UDP increased mRNA expression and activity of inducible nitric oxide synthase and interleukin-6 in J774 macrophages; this effect was blocked by suramin (100-300 mu M) or pyridoxal-phosphate-6-azophenyl-2'-4'-disulphonic acid (PPADS, 10-30 mu M). Finally, 4-week treatment of cholesterol-fed apoE(-/-) mice with suramin or PPADS (50 and 25 mg.kg(-1).day(-1) respectively) reduced plaque size, without changing plaque composition (relative SMC and macrophage content) or cell replication.Conclusions and implications: These results suggest involvement of nucleotide receptors, particularly P2Y(6) receptors, during atherosclerosis, and warrant further research with selective purinoceptor antagonists or P2Y(6) receptor-deficient mice. British Journal of Pharmacology (2010) 159, 326-336; doi: 10.1111/j.1476-5381.2009.00497.x; published online 24 December 2009