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1-磷酸鞘氨醇（S1 P）和肿瘤坏死因子（TNF）α诱导的内皮细胞粘附分子（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。HDL抑制S1 P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的行动与一氧化氮合酶（NOS）的激活，并逆转磷脂酰肌醇3-激酶和NOS的抑制剂。HDL诱导的抑制作用也被I型B类清道夫受体（SR-BI）及其相关蛋白PDZK 1的下调所减弱。当TNF α被用作刺激物时，HDL诱导的NOS激活和对粘附分子表达的抑制作用部分地被S1 P受体表达的下调所减弱，特别是S1 P（1），以及SR-BI。主要由载脂蛋白A-I和磷脂酰胆碱组成的重组HDL模拟HDL诱导作用的SR-BI敏感部分。S1 P（3）受体的下调严重抑制了S1 P的刺激作用。虽然G（I/o）蛋白可能在刺激或抑制S1 P作用中发挥作用，但从百日咳毒素敏感性判断，S1 P（3）受体与G（12/13）蛋白的偶联可能是区分刺激途径与抑制途径的关键。总之，即使S1 P单独刺激粘附分子表达，HDL通过涉及磷脂酰肌醇3-激酶和NOS的SR-BI/PDZK 1介导的信号通路克服S1 P（3）受体介导的刺激作用。此外，HDL的S1 P组分通过S1 P受体，特别是S1 P，在抑制TNF α诱导的作用中起作用（1）。

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 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

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

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