Regulation of VCAM-1 and ICAM-1 expression in atherogenesis

动脉粥样硬化形成中 VCAM-1 和 ICAM-1 表达的调节

• 批准号: 06671022
• 负责人: KUME Noriaki
• 金额: $ 1.28万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06671022/
• 关键词: atherosclerosis; endothelium; adhesion molecules; growth factors; lysophosphatidylcholine; oxidized LDL; cyclic AMP; サイクリックAMP

Endothelial expression of mononuclear leukocyte adhesion molecules, such as VCAM-1, and ICAM-1, has been implicated in molecular mechanism involved in the recruitment of blood monocytes and lymphocytes into early atherosclerotic lesions. In the advanced lesions, migration and proliferation of medial smooth muscle cells into arterial intima are observed, and endothelial production of growth factors directed to smooth muscle cells appears to play a role in this process. We have identified lysophosphatidylcholine, a phospholipid component of atherogenic lipoproteins, such as oxidized LDL and beta-VLDL, as a candidate to activate endothelium to induce expression of adhesion molecules and growth factors, including VCAM-, ICAM-1, PDGF-A and -B chains and HB-EGF.In this research project, we have explored the signal transduction and transcriptional regulatory mechanisms responsible for lyso-PC-induced gene expression in cultured vascular endothelial cells. Our study revealed that activation of protein kinase C does not appear to be involved in lyso-PC-induced endothelial PDGF and ICAM-1 expression ; however, elevated levels of intracellular cyclic AMP inhibited the effect of lyso-PC.We have also found that certain protein can be rapidly tyrosine phosphorylated in response to activation with lyso-PC.Regarding to the transcriptional regulation by lyso-PC,our gel shift assays showed that lyso-PC did not activate NFkappaB but timedependently activate AP-1 to some extent.

单核细胞黏附分子如VCAM-1和ICAM-1的内皮表达参与了单核细胞和淋巴细胞重新聚集到早期动脉粥样硬化病变的分子机制。在晚期病变中，可观察到中层平滑肌细胞迁移和增殖进入动脉内膜，内皮细胞产生的针对平滑肌细胞的生长因子似乎在这一过程中发挥了作用。溶血磷脂酰胆碱是氧化低密度脂蛋白和极低密度脂蛋白等致动脉粥样硬化脂蛋白中的一种磷脂成分，可以激活内皮细胞，诱导血管内皮细胞黏附分子和生长因子的表达，包括VCAM-1、ICAM-1、PDGF-A和-B链和HB-EGF。我们的研究发现，蛋白激酶C的激活似乎不参与Lyso-PC诱导的内皮细胞PDGF和ICAM-1的表达；然而，细胞内环状AMP水平的升高抑制了Lyso-PC的作用。我们还发现，某些蛋白质可以被Lyso-PC激活而迅速被酪氨酸磷酸化。关于Lyso-PC的转录调控，我们的凝胶位移分析表明Lyso-PC不激活NFkappaB，但在一定程度上依赖于时间而激活AP-1。

项目成果

Hiroshi Ochi, Noriaki Kume, Eiichiro Nishi, Toru Kita.: "Elevated levels of cAMP inhibit protein kinase C-independent mechanisms of endothelial PDGF-B chain and ICAM-1 upregulation by lysophosphatidyl-choline" Circulation Research. 77. 530-535 (1995)

Hiroshi Ochi、Noriaki Kume、Eiichiro Nishi、Toru Kita.：“cAMP 水平升高抑制内皮 PDGF-B 链的蛋白激酶 C 独立机制和溶血磷脂酰胆碱上调 ICAM-1”循环研究。

Noriaki Kume et al: "Involvement of protein kinse C-independent mechanisms in endothelial ICAM-1 up-regulation by lysophosphatidylcholine." Annals of New York Academy of Sciences. 748. 541-542 (1995)

Noriaki Kume 等人：“蛋白质激酶 C 独立机制参与溶血磷脂酰胆碱上调内皮细胞 ICAM-1。”

Hiroshi Ochi et al: "Elevated levels of cAMP inhibit protein kinase C-independent mechanisms of endothelial PDGF-B chain and ICAM-1 uprequlation by lysophosphatidylcholine" Circulation Research. 77. 530-535 (1995)

Hiroshi Ochi 等人：“cAMP 水平升高会抑制内皮 PDGF-B 链的蛋白激酶 C 独立机制和溶血磷脂酰胆碱上调 ICAM-1”循环研究。

Noriaki Kume et al: "Involvement of protein kinase C-independent mechanisms in endothelial ICAM-1 upregulation by lysophosphatidylcholine" Annals of the New York Academy of Sciences. 748. 541-542 (1995)

Noriaki Kume 等人：“溶血磷脂酰胆碱上调内皮 ICAM-1 中蛋白激酶 C 独立机制的参与”纽约科学院年鉴。

Noriaki Kume, Hiroshi Ochi, Eiichiro Nishi, Michael A.Gimbrone, Jr., Toru Kita.: "Involvement of protein kinase C-independent mechanisms in endothelial ICAM-1 upregilation by lysophosphatidyl-choline" Ann, N.Y.Acad.Sci.748. 541-542 (1995)

Noriaki Kume、Hiroshi Ochi、Eiichiro Nishi、Michael A.Gimbrone, Jr.、Toru Kita.：“溶血磷脂酰胆碱导致内皮 ICAM-1 上调中蛋白激酶 C 独立机制的参与”Ann，N.Y.Acad.Sci.748。