Antiatherogenic effects of high density lipoprotein and sphingosine 1-phosphate

高密度脂蛋白和1-磷酸鞘氨醇的抗动脉粥样硬化作用

基本信息

批准号：
18590973
负责人：
KIMURA Takao
金额：
$ 2.49万
依托单位：
Gunma University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

We clarified 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 kappaB activation and adhesion molecule expression in human umbilical vein endothelial cells. The inhibitory HDL actions were associated with nitricoxide 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 TNFalpha 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 summary, even though S1P alone stimulates adhesion molecule expression, HDL overcomes S1P(3) receptormediated 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 TNFalpha-induced actions through S1P receptors, especially S1P(1).

We clarified 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抑制了人脐静脉内皮细胞中S1P诱导的核因子Kappab激活和粘附分子的表达。抑制性HDL作用与硝酸合酶（NOS）激活有关，并被磷脂酰肌醇3-激酶和NOS抑制剂逆转。 HDL诱导的抑制作用也通过下调B类B类（SR-BI）及其相关蛋白PDZK1的下调来减弱。当将TNFalphA用作刺激剂时，HDL诱导的NOS激活和对粘附分子表达的抑制作用部分通过S1P受体的表达下调，尤其是S1P（1），除了SR-BI外，还会减弱。重建的HDL主要由载脂蛋白A-I和磷脂酰胆碱组成，模仿了HDL诱导的作用的SR-BI敏感部分。 S1P（3）受体的下调严重抑制了S1P的刺激作用。尽管G（I/O）蛋白可能在刺激性或抑制性S1P作用中起作用，从百日咳毒素敏感性判断，但S1P（3）受体与G（12/13）蛋白的偶联对于区分刺激途径与抑制性途径可能是至关重要的。总而言之，即使单独使用S1P刺激了粘附分子的表达，HDL也通过SR-BI/PDZK1介导的信号传导途径克服了S1P（3）受体介导的刺激作用，涉及涉及磷脂酰肌醇3-激酶和NOS。此外，HDL的S1P成分在通过S1P受体（尤其是S1P）抑制TNFalpha诱导的作用中起作用（1）。

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Sphingosine 1-phosphate receptors mediate stimulatory and inhibitory signalings for expression of adhesion molecules in endothelial cells

DOI：
10.1016/j.cellsig.2005.07.011
发表时间：
2006-06-01
期刊：
CELLULAR SIGNALLING
影响因子：
4.8
作者：
Kimura, T;Tomura, H;Okajima, F
通讯作者：
Okajima, F

High density lipoprotein inhibits adhesion molecule expression via scavenger receptor class B type I and sphingosine 1-phosphate specific receptors, S1P1 and S1P3 in endothelial cells

高密度脂蛋白通过内皮细胞中 B 类清道夫受体 I 型和鞘氨醇 1-磷酸特异性受体 S1P1 和 S1P3 抑制粘附分子表达

DOI：
发表时间：
2007
期刊：
影响因子：
0
作者：
Kimura Takao;Murakami Masami;Okajima Fumikazu
通讯作者：
Okajima Fumikazu

Previously postulated "ligand-independent" signaling of GPR4 is mediated through proton-sensing mechanisms.

DOI：
10.1016/j.cellsig.2007.03.009
发表时间：
2007-08
期刊：
Cellular signalling
影响因子：
4.8
作者：
M. Tobo;H. Tomura;C. Mogi;Ju-Qiang Wang;Jin-Peng Liu;Mayumi Komachi;A. Damirin;Takao Kimura;N. Murata;H. Kurose;Koichi Sato;F. Okajima
通讯作者：
M. Tobo;H. Tomura;C. Mogi;Ju-Qiang Wang;Jin-Peng Liu;Mayumi Komachi;A. Damirin;Takao Kimura;N. Murata;H. Kurose;Koichi Sato;F. Okajima

血管内皮細胞における高密度リポ蛋白質の接着分子発現抑制作用〜HDL受容体SR-BIとS1P受容体の役割

高密度脂蛋白对血管内皮细胞粘附分子表达的抑制作用~HDL受体SR-BI和S1P受体的作用