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

• 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
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590973/
• 关键词: Atherosclerosis; High Density Lipoprotein; Sphingosine 1-phosphate; Endothelial Cell; Nitric Oxide; Adhesion Molecule; 高密度リボ蛋白質HDL; 生理活性物質; 高密度リポ蛋白質(HDL); スフィンゴシン1-リン酸(S1P); Scanvenger Receptor Class B type I(SR-BI); G蛋白質

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).

我们阐明了高密度脂蛋白（HDL）抑制鞘氨醇1-磷酸（S1P）和肿瘤坏死因子(TNF) α在内皮细胞中诱导的粘附分子（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酶（NOS）的激活有关，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清道夫受体B类I型（SR-BI）及其相关蛋白PDZK1而减弱。当使用TNFalpha作为刺激剂时，除了SR-BI外，通过下调S1P受体的表达，尤其是S1P(1)的表达，部分减弱了hdl诱导的NOS激活和对粘附分子表达的抑制作用。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，尽管S1P单独刺激粘附分子表达，但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tnfalpha诱导的作用中发挥作用。

项目成果

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

• 发表时间: 2007
• 作者: Kimura Takao;Murakami Masami;Okajima Fumikazu
• 通讯作者: Okajima Fumikazu

Role of scavenger receptor class B type 1 and sphingosine 1-phosphate receptors in high density lipoprotein-induced inhibition of adhesion molecule expression in endothelial cells.

1 型 B 类清道夫受体和 1-磷酸鞘氨醇受体在内皮细胞高密度脂蛋白诱导的粘附分子表达抑制中的作用。

• 发表时间: 2006
• 期刊: J Biol Chem. 281・49
• 作者: Kimura T;Tomura H;Mogi C;Kuwabara A;Damirin A;Ishizuka T;Sekiguchi A;Ishiwara M;Im DS;Sato K;Murakami M;Okajima F
• 通讯作者: Okajima F

Role of lipoprotein-associated lysophospholipids in migratory activity of coronary artery smooth muscle cells

• DOI: 10.1152/ajpheart.00865.2006
• 发表时间: 2007-05-01
• 期刊: AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
• 影响因子: 4.8
• 作者: Damirin, Alatangaole;Tomura, Hideaki;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