Hydrogen peroxide induces S1P1 receptors and sensitizes vascular endothelial cells to sphingosine 1-phosphate, a platelet-derived lipid mediator
Hydrogen peroxide induces S1P1 receptors and sensitizes vascular endothelial cells to sphingosine 1-phosphate, a platelet-derived lipid mediator
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DOI：
10.1152/ajpcell.00117.2006
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发表时间：
2007-02-01
影响因子：
5.5
通讯作者：
Kosaka, Hiroaki
中科院分区：
文献类型：
--
作者：
Igarashi, Junsuke;Miyoshi, Megumi;Kosaka, Hiroaki
鞘氨醇1-磷酸（S1 P）是一种血小板衍生的血管生成脂质生长因子，调节G蛋白偶联的S1 P（1）受体（S1 P（1）-R）以激活内皮细胞中的内皮一氧化氮合酶（eNOS）以及MAPK途径。我们探讨过氧化氢（H2 O2），一种代表性的活性氧，是否以及如何改变S1 P（1）-R的表达和影响S1 P信号在培养的牛主动脉内皮细胞（BAECs）。当BAEC用病理生理相关浓度的H2 O2处理（150 μ M，30分钟）时，S1 P（1）-R蛋白表达水平以剂量依赖性方式急剧增加约30倍。当BAEC已经用H2 O2预处理时，随后的S1 P刺激（100 nM）导致更高程度的eNOS酶活化（评估为细胞内cGMP含量，1.7 +/- 0.2倍vs.无H2 O2预处理组，P < 0.05），与eNOS和MAPK ERK 1/2的更高幅度的磷酸化反应相关。Src家族酪氨酸激酶抑制剂PP 2可阻断H2 O2对S1 P（1）-R蛋白表达的上调作用和增强BAEC对S1 P的反应。H2 O2不增加S1 P（1）mRNA的表达，而在相同的培养条件下，VEGF导致S1 P（1）mRNA信号的增加。而H2 O2减弱BAECs的增殖，此外S1 P恢复这些细胞的生长反应。这些结果表明，细胞外给予H2 O2增加S1 P（1）-R的表达，并促进后续S1 P治疗的内皮反应。这些结果可能会确定潜在的重要点之间的串扰活性氧和鞘脂途径在血管反应。
Sphingosine 1-phosphate (S1P) is a platelet-derived angiogenic lipid growth factor, modulating G-protein-coupled S1P(1) receptors (S1P(1)-R) to activate endothelial nitric oxide synthase (eNOS), as well as MAPK pathways in endothelial cells. We explored whether and how hydrogen peroxide (H2O2), a representative reactive oxygen species, alters S1P(1)-R expression and influences S1P signaling in cultured bovine aortic endothelial cells (BAECs). When BAECs are treated with pathophysiologically relevant concentrations of H2O2 (150 mu M for 30 min), S1P(1)-R protein expression levels are acutely augmented by similar to 30-fold in a dose-dependent fashion. When BAECs have been pretreated with H2O2, subsequent S1P stimulation (100 nM) leads to a higher degree of eNOS enzyme activation (assessed as intracellular cGMP content, 1.7 +/- 0.2-fold vs. no H2O2 pretreatment groups, P < 0.05), associated with a higher magnitude of phosphorylation responses of eNOS and MAPK ERK1/2. PP2, an inhibitor of Src-family tyrosine kinase, abolished the effects of H2O2 on both S1P(1)-R protein upregulation and enhanced BAEC responses to S1P. H2O2 does not augment S1P(1) mRNA expression, whereas VEGF under identical cultures leads to increases in S1P(1) mRNA signals. Whereas H2O2 attenuates proliferation of BAECs, addition of S1P restores growth responses of these cells. These results demonstrate that extracellularly administered H2O2 increases S1P(1)-R expression and promotes endothelial responses for subsequent S1P treatment. These results may identify potentially important points of cross-talk between reactive oxygen species and sphingolipid pathways in vascular responses.