| Project/Area Number |
03670460
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Kumamoto University Hospital |
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Principal Investigator |
KUGIYAMA Kiyotaka Kumamoto University Hospital, Division of Cardiology, Assistant Professor, 医学部附属病院, 助手 (00225129)
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| Co-Investigator(Kenkyū-buntansha) |
OGAWA Hisao Kumamoto University Hospital, Division of Cardiology, Lecturer, 医学部附属病院, 講師 (50177135)
YASUE Hirofumi Kumamoto University Hospital, Division of Cardiology, Professor, 医学部附属病院, 教授 (40174502)
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| Project Period (FY) |
1991 – 1992
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| Project Status |
Completed (Fiscal Year 1992)
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| Budget Amount *help |
¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 1992: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1991: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Keywords | Oxidized LDL / endothelial cells / endothelium-dependent vasorelaxation / lysophosphatidylcholine / fibrinolysis / intercellular adhesion molecule-1 / protein kinase C / Intercellular adhesion molecule-1 / Polymorphonuclear Leukecyte / endothelial cell / oxidized LDL / endothelin / fibrinolysis / protein kinase C |
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| Research Abstract |
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
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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
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