Uridine adenosine tetraphosphate (Up4A) is a strong inductor of smooth muscle cell migration via activation of the P2Y2 receptor and cross-communication to the PDGF receptor.
Uridine adenosine tetraphosphate (Up4A) is a strong inductor of smooth muscle cell migration via activation of the P2Y2 receptor and cross-communication to the PDGF receptor.
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DOI：
10.1016/j.bbrc.2011.12.088
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发表时间：
2012-01
影响因子：
3.1
通讯作者：
A. Wiedon;M. Tölle;Joschika Bastine;M. Schuchardt;Tao-Ming Huang;V. Jankowski;J. Jankowski;W. Zidek;M. van der Giet
中科院分区：
文献类型：
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作者：
A. Wiedon;M. Tölle;Joschika Bastine;M. Schuchardt;Tao-Ming Huang;V. Jankowski;J. Jankowski;W. Zidek;M. van der Giet
最近发现的尿苷腺苷四磷酸二核苷酸(UP4A)是在人血浆中发现的，其特征是内皮源性血管收缩因子(EDCF)。进一步研究发现，UP4A与血管平滑肌细胞(VSMC)增殖呈正相关。由于迁移在动脉粥样硬化病变形成中的主导作用，我们的目的是研究uP4A的迁移刺激潜力。事实上，我们通过使用改进的Boyden小室发现了UP4A对VSMC的强烈趋化作用。这种迁移在很大程度上依赖于骨桥蛋白分泌(OPN)，在与OPN阻断的抗体同时孵育时，迁移信号减少到23%。由于使用特定和非特异的嘌呤受体抑制剂的抑制模式，Up4A主要通过P2Y2来调节其迁移信号。用Luminex技术研究了该受体背后的信号转导，发现ERK1/2途径被激活。利用PDGFR特异性抑制剂AG1296和针对PDGFR-β的小干扰RNA技术，我们发现经uP4A刺激后，PDGFR-β基因敲除细胞的迁移信号较对照细胞明显减少。在这项研究中，我们提供了大量数据，UP4A显示出迁移刺激潜力，可能涉及MEK1和ERK1/2以及基质蛋白OPN的信号级联。我们进一步认为，迁移过程的启动主要是通过UP4A直接激活P2Y2和反式激活PDGFR来进行的。
The recently discovered dinucleotide uridine adenosine tetraphosphate (Up4A) was found in human plasma and characterized as endothelium-derived vasoconstrictive factor (EDCF). A further study revealed a positive correlation between Up4A and vascular smooth muscle cell (VSMC) proliferation. Due to the dominant role of migration in the formation of atherosclerotic lesions our aim was to investigate the migration stimulating potential of Up4A. Indeed, we found a strong chemoattractant effect of Up4A on VSMC by using a modified Boyden chamber. This migration dramatically depends on osteopontin secretion (OPN) revealed by the reduction of the migration signal down to 23% during simultaneous incubation with an OPN-blocking antibody. Due to inhibitory patterns using specific and unspecific purinoreceptor inhibitors, Up4A mediates it’s migratory signal mainly via the P2Y2. The signaling behind the receptor was investigated with luminex technique and revealed an activation of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) pathway. By use of the specific PDGF receptor (PDGFR) inhibitor AG1296 and siRNA technique against PDGFR-β we found a strongly reduced migration signal after Up4A stimulation in the PDGFR-β knockdown cells compared to control cells. In this study, we present substantiate data that Up4A exhibits migration stimulating potential probably involving the signaling cascade of MEK1 and ERK1/2 as well as the matrix protein OPN. We further suggest that the initiation of the migration process occurs predominant through direct activation of the P2Y2by Up4A and via transactivation of the PDGFR.