Role of scavenger receptor class B type I and sphingosine 1-phosphate receptors in high density lipoprotein-induced inhibition of adhesion molecule expression in endothelial cells
Role of scavenger receptor class B type I and sphingosine 1-phosphate receptors in high density lipoprotein-induced inhibition of adhesion molecule expression in endothelial cells
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DOI：
10.1074/jbc.m605823200
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发表时间：
2006-12-08
影响因子：
4.8
通讯作者：
Okajima, Fumikazu
中科院分区：
文献类型：
--
作者：
Kimura, Takao;Tomura, Hideaki;Okajima, Fumikazu
我们表征了高密度脂蛋白（HDL）抑制内皮细胞中由鞘氨醇1-磷酸（S1P）和肿瘤坏死因子(TNF) α诱导的粘附分子（包括血管细胞粘附分子-1和细胞间粘附分子-1）表达的分子机制。高密度脂蛋白抑制s1p诱导的人脐静脉内皮细胞核因子κ B活化和粘附分子表达。抑制HDL的作用与一氧化氮合成酶（NOS）的激活有关，并被磷脂酰肌醇3-激酶和NOS抑制剂逆转。抑制HDL诱导的抑制作用也通过下调清道夫受体B类I型（SR-BI）及其相关蛋白PDZK1而减弱。当TNF - α作为刺激剂使用时，除了SR-BI外，hdl诱导的NOS激活和对粘附分子表达的抑制作用部分被下调S1P受体的表达，尤其是S1P(1)的表达而减弱。重组HDL主要由载脂蛋白A-I和磷脂酰胆碱组成，模拟了sr - bi对HDL诱导作用的敏感部分。S1P(3)受体下调严重抑制了S1P的刺激作用。虽然G（i/o）蛋白可能在刺激或抑制S1P作用中发挥作用，但根据百日咳毒素敏感性判断，S1P(3)受体与G（12/13）蛋白的偶联可能是区分刺激途径和抑制途径的关键。综上所述，即使S1P单独刺激粘附分子表达，HDL通过SR-BI/ pdzk1介导的信号通路，包括磷脂酰肌醇3-激酶和NOS，克服了S1P(3)受体介导的刺激作用。此外，HDL的S1P成分通过S1P受体，特别是S1P(1)，在抑制TNF α诱导的作用中发挥作用。
We characterized the molecular mechanisms by which high density lipoprotein (HDL) inhibits the expression of adhesion molecules, including vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, induced by sphingosine 1-phosphate (S1P) and tumor necrosis factor (TNF) alpha in endothelial cells. HDL inhibited S1P-induced nuclear factor kappa B activation and adhesion molecule expression in human umbilical vein endothelial cells. The inhibitory HDL actions were associated with nitric-oxide synthase (NOS) activation and were reversed by inhibitors for phosphatidylinositol 3-kinase and NOS. The HDL-induced inhibitory actions were also attenuated by the down-regulation of scavenger receptor class B type I (SR-BI) and its associated protein PDZK1. When TNF alpha was used as a stimulant, the HDL-induced NOS activation and the inhibitory action on adhesion molecule expression were, in part, attenuated by the down-regulation of the expression of S1P receptors, especially S1P(1), in addition to SR-BI. Reconstituted HDL composed mainly of apolipoprotein A-I and phosphatidylcholine mimicked the SR-BI-sensitive part of HDL-induced actions. Down-regulation of S1P(3) receptors severely suppressed the stimulatory actions of S1P. Although G(i/o) proteins may play roles in either stimulatory or inhibitory S1P actions, as judged from pertussis toxin sensitivity, the coupling of S1P(3) receptors to G(12/13) proteins may be critical to distinguish the stimulatory pathways from the inhibitory ones. In conclusion, even though S1P alone stimulates adhesion molecule expression, HDL overcomes S1P(3) receptor-mediated stimulatory actions through SR-BI/PDZK1-mediated signaling pathways involving phosphatidylinositol 3-kinase and NOS. In addition, the S1P component of HDL plays a role in the inhibition of TNF alpha-induced actions through S1P receptors, especially S1P(1).