Effects of oxidized low density lipoprotein on vascular endothelial and smooth muscle cells

氧化低密度脂蛋白对血管内皮和平滑肌细胞的影响

• 批准号: 03670460
• 负责人: KUGIYAMA Kiyotaka
• 金额: $ 1.54万
• 依托单位: Kumamoto University Hospital
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1991
• 资助国家: 日本
• 起止时间: 1991 至 1992
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-03670460/
• 关键词: Oxidized LDL; endothelial cells; endothelium-dependent vasorelaxation; lysophosphatidylcholine; fibrinolysis; intercellular adhesion molecule-1; protein kinase C; Intercellular adhesion molecule-1; Polymorphonuclear Leukecyte; endothelial cell

Lysophosphatidylcholine (LPC) transferred from oxidatively modified low density lipoprotein (Ox-LDL) to the endothelial surface membrane has been shown to produce a selective unresponsiveness to cell surface receptor-regulated endothelium-dependent relaxation (EDR) in the rabbit aorta and porcine coronary artery. To determine its mechanism, the effects of LPC or Ox-LDL on intracellular signals in endothelial cells were examined. The results from this experiment indicate that LPC inhibits the early transmembrane signaling pathway in endothelial cells, and Protein Kinase C (PKC) activation could at least partially be involved in the negative regulation by LPC. These intracellular actions of LPC may play a role in the mechanism of the LPC-induced impairment of EDR in response to cell surface receptor-mediated stimulations.To determine whether Ox-LDL modulates endothelial fibrinolytic system, levels of plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (t-PA) a … More ntigens in the conditioned medium were measured by ELISA. The results indicate that Ox-LDL stimulates PAI-1 release by the transferable hydrophilic lipid(s) in Ox-LDL, especially LPC, while Ox-LDL inhibits t-PA release by 25-hydroxycholesterol and 7-ketocholesterol or other transferable lipid(s) from Ox-LDL to albumin rather than LPC. Thus, lipid products in Ox-LDL may impair endothelial fibrinolysis. We further examined the effects of Ox-LDL on the secretion of endothelin-1-like immunoreactivity (ET-1-LI) by the cultured vascular endothelial cells (porcine aortic endothelial cells and human umbilical vein endothelial cells), considering the possible relevance of ET-1 to the atherosclerosis and hypercholesterolemia. The results show that LPC in Ox-LDL causes suppression of ET-1-LI release, which may counteract the vasoconstricitve properties of atherosclerotic arteries. Furthermore, LPC in Ox-LDL causes the increase of the endothelial adhesiveness to polymorphonuclear leukocytes (PMNs), which augments PMNs-induced impairment of EDR in porcine coronary artery. This is due to increased expression of intercellular adhesion molecule-1 in endothelium of the porcine coronary artery, and the activation of PKC by LPC in Ox-LDL may at least in part be involved in these mechanisms. Less

氧化修饰低密度脂蛋白（Ox-LDL）的溶血磷脂酰胆碱（LPC）转移到内皮细胞表面膜上，对细胞表面受体调节的内皮依赖性舒张反应（EDR）产生选择性无反应。为了确定其机制，检测LPC或Ox-LDL对内皮细胞内信号的影响。本实验结果表明，LPC抑制内皮细胞早期跨膜信号通路，蛋白激酶C（PKC）的激活至少部分参与了LPC的负性调节。为了确定Ox-LDL是否对内皮纤溶系统有调节作用，测定了内皮细胞中纤溶酶原激活物抑制剂-1（派-1）和组织型纤溶酶原激活物（t-PA）的水平，并与对照组比较。 ...更多信息 通过ELISA测量条件培养基中的抗原。结果表明，Ox-LDL通过其可转移的亲水性脂质，尤其是LPC，刺激派-1的释放，而通过25-羟基胆固醇和7-酮基胆固醇等可转移脂质，Ox-LDL抑制t-PA的释放。因此，Ox-LDL中的脂质产物可能损害内皮纤维蛋白溶解。我们进一步研究了Ox-LDL对培养的血管内皮细胞（猪主动脉内皮细胞和人脐静脉内皮细胞）分泌内皮素-1样免疫反应性（ET-1-LI）的影响，认为ET-1可能与动脉粥样硬化和高胆固醇血症有关。结果表明，Ox-LDL中LPC抑制ET-1-LI的释放，可能与动脉粥样硬化的缩血管作用有关。Ox-LDL中的LPC可引起猪冠状动脉内皮细胞对多形核白细胞（PMNs）的依赖性增加，从而加重PMNs对猪冠状动脉EDR的损伤。这是由于细胞间粘附分子-1在猪冠状动脉内皮细胞中的表达增加，并且Ox-LDL中LPC激活PKC可能至少部分参与这些机制。少

项目成果

Michihisa Jougasaki et al.: "Suppression of endothelin-1 secretion by lysophosphatidylcholine in oxidized low density lipoprotein in cultured vascular endothelial cells" Circulation Research. 71. 614-619 (1992)

Michihisa Jougasaki 等人：“培养血管内皮细胞中氧化低密度脂蛋白中溶血磷脂酰胆碱对内皮素 1 分泌的抑制”循环研究。

Kiyotaka Kugiyam,et al.: "Stimulation of plasminogen activator inhibitor-1 (PAI-1) and inhibition of tissue plasminogen activator (tPA) release from endothelial cells by lipid products in oxidized LDL (Ox-LDL)" Circulation. 86 suppl.I. 211 (1992)

Kiyotaka Kugiyam 等人：“氧化 LDL (Ox-LDL) 中的脂质产物刺激纤溶酶原激活剂抑制剂-1 (PAI-1) 并抑制内皮细胞释放组织纤溶酶原激活剂 (tPA)”。

Kiyotaka Kugiyama,et al.: "Lysophosphatidylcholine inhibits surface receptor-mediated intra-cellular signals in endothelial cells by a pathway involving protein kinase C activation" Circulation Research. 71. 1422-1428 (1992)

Kiyotaka Kugiyama 等人：“溶血磷脂酰胆碱通过涉及蛋白激酶 C 激活的途径抑制内皮细胞中表面受体介导的细胞内信号”循环研究。

Michihisa Jougasaki, et al.: "Suppression of endothelin-l secretion by lysophosphatidylcholine in oxidized low density lipoprotein in cultured vascular endothelial cells" Circulation Research. 71. 614-619 (1992)

Michihisa Jougasaki 等人：“培养的血管内皮细胞中氧化低密度脂蛋白中溶血磷脂酰胆碱对内皮素-1 分泌的抑制”循环研究。

Kiyotaka Kugiyama: "Atrial and brain natriuretic peptides(ANP and BNP)prevent endothelial cytotoxicity of lysophosphatidylcholine" Circulation. 84. II-629 (1991)

Kiyotaka Kugiyama：“心房和脑钠尿肽（ANP 和 BNP）可防止溶血磷脂酰胆碱的内皮细胞毒性”循环。