EETs Attenuate Ox-LDL-Induced LTB4 Production and Activity by Inhibiting p38 MAPK Phosphorylation and 5-LO/BLT1 Receptor Expression in Rat Pulmonary Arterial Endothelial Cells.
EETs Attenuate Ox-LDL-Induced LTB4 Production and Activity by Inhibiting p38 MAPK Phosphorylation and 5-LO/BLT1 Receptor Expression in Rat Pulmonary Arterial Endothelial Cells.
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DOI：
10.1371/journal.pone.0128278
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Yan XF
中科院分区：
文献类型：
--
作者：
Jiang JX;Zhang SJ;Xiong YK;Jia YL;Sun YH;Lin XX;Shen HJ;Xie QM;Yan XF
细胞色素P-450环氧合酶（EPOX）衍生的环氧二十碳三烯酸（EPOX）、5-脂氧合酶（5-LO）和5-LO的产物白三烯B4（LTB 4）都在血管炎症过程中起关键作用。我们以前已经表明，依地平可以减轻氧化低密度脂蛋白（ox-LDL）诱导的原代大鼠肺动脉内皮细胞（RPAECs）的内皮炎症。在这里，我们研究了ox-LDL是否可以通过5-LO途径促进LTB 4的产生。我们进一步探讨了外源性雌二醇如何影响ox-LDL诱导的LTB 4的产生和活性。我们发现，用ox-LDL处理增加了LTB 4的产生，并进一步导致单核细胞趋化蛋白-1（MCP-1/CCL 2）和细胞间粘附分子-1（ICAM-1）的表达和释放。11，12-EET和14，15-EET可抑制5-LO通路，从而减弱ox-LDL诱导的上述变化。此外，LTB 4受体1（BLT 1受体）拮抗剂U 75302减弱ox-LDL诱导的ICAM-1和MCP-1/CCL 2的表达和产生，而LTB 4受体2（BLT 2受体）拮抗剂LY 255283则无此作用。此外，我们还证实ox-LDL处理后RPAEC中5-LO和BLT 1的表达增加是通过p38丝裂原活化蛋白激酶（MAPK）途径激活核因子-κB（NF-κB）所致。我们的研究结果表明，Eclase通过下调5-LO/BLT 1受体途径抑制ox-LDL诱导的LTB 4产生和随后的炎症反应，其中p38 MAPK磷酸化激活NF-κB。这些结果表明，通过5-LO和EPOX途径的花生四烯酸的代谢可能是血管内皮细胞的生理调节的相互制约。
Cytochrome P-450 epoxygenase (EPOX)-derived epoxyeicosatrienoic acids (EETs), 5-lipoxygenase (5-LO), and leukotriene B4 (LTB4), the product of 5-LO, all play a pivotal role in the vascular inflammatory process. We have previously shown that EETs can alleviate oxidized low-density lipoprotein (ox-LDL)-induced endothelial inflammation in primary rat pulmonary artery endothelial cells (RPAECs). Here, we investigated whether ox-LDL can promote LTB4 production through the 5-LO pathway. We further explored how exogenous EETs influence ox-LDL-induced LTB4 production and activity. We found that treatment with ox-LDL increased the production of LTB4 and further led to the expression and release of both monocyte chemoattractant protein-1 (MCP-1/CCL2) and intercellular adhesion molecule-1 (ICAM-1). All of the above ox-LDL-induced changes were attenuated by the presence of 11,12-EET and 14,15-EET, as these molecules inhibited the 5-LO pathway. Furthermore, the LTB4 receptor 1 (BLT1 receptor) antagonist U75302 attenuated ox-LDL-induced ICAM-1 and MCP-1/CCL2 expression and production, whereas LY255283, a LTB4 receptor 2 (BLT2 receptor) antagonist, produced no such effects. Moreover, in RPAECs, we demonstrated that the increased expression of 5-LO and BLT1 following ox-LDL treatment resulted from the activation of nuclear factor-κB (NF-κB) via the p38 mitogen-activated protein kinase (MAPK) pathway. Our results indicated that EETs suppress ox-LDL-induced LTB4 production and subsequent inflammatory responses by downregulating the 5-LO/BLT1 receptor pathway, in which p38 MAPK phosphorylation activates NF-κB. These results suggest that the metabolism of arachidonic acid via the 5-LO and EPOX pathways may present a mutual constraint on the physiological regulation of vascular endothelial cells.
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影响因子：
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作者：
Kim N;Luster AD
通讯作者：
Luster AD
影响因子：
3
作者：
Okunishi, Katsuhide;Peters-Golden, Marc
通讯作者：
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1161/01.atv.0000172632.96987.2d
发表时间：
2005-08-01
影响因子：
8.7
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Hammock, Bruce D.