The role of endothelial lipase in pathogenesis of atherosclerosis : A novel therapeutic target for raising HDL cholesterol
| Project/Area Number |
16390226
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Kobe University |
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Principal Investigator |
YOKOYAMA Mitsuhiro Kobe University, Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (40135794)
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| Co-Investigator(Kenkyū-buntansha) |
KAWASHIMA Seinosuke Kobe University, Graduate School of Medicine, Associate Professor, 大学院・医学系研究科, 助教授 (10177678)
HIRATA Ken-ichi Kobe University, Kobe University, Hospital, Lecturer, 医学部附属病院, 講師 (20283880)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥14,100,000 (Direct Cost: ¥14,100,000)
Fiscal Year 2005: ¥6,700,000 (Direct Cost: ¥6,700,000)
Fiscal Year 2004: ¥7,400,000 (Direct Cost: ¥7,400,000)
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| Keywords | lipoprotein / atherosclerosis / inflammation / endothelial cell / HDL cholesterol / knockout mouse / cytokine / lipase / リポ蛋白 / 急性心筋梗塞 / 遺伝子多型 / 血管内皮細胞 / マクロファージ / 血管平滑筋 |
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| Research Abstract |
Recently, we have cloned endothelial cell-derived lipase (EL), a new member of the lipase gene family, from endothelial cells during vascular formation. To investigate role of EL in lipoprotein metabolism and atherosclerosis, we generated transgenic and knockout mice of EL, and analyzed the lipid profiles. Characterization of EL transgenic and knockout mice revealed that EL expression correlates inversely with circulating HDL-C levels in genetic mouse models. To investigate the role of EL in atherosclerotic progression, apoE/EL double knockout mice were generated and analyzed. Atherosclerotic lesion area was decreased by 70% in the EL/apoE double knockout mice compared with the apoE single knockout mice. Despite the increase in plasma cholesterol, EL/apoE double knockout mice showed significantly decreased aortic plaque sizes. EL may have atherogenic actions in vivo through its effect on circulating HDL cholesterol and non-enzymatic bridging function. EL mRNA was upregulated in endothelial cells by inflammatory cytokines implicated in vascular disease etiology, including TNF-α and IL-1β. Immunohistochemical analysis revealed that EL was expressed in endothelial and smooth muscle cells, as well as infiltrating cells, in the atheromatous plaque in human coronary arteries. In EL knockout mice, acute inflammatory reaction by LPS injection did not affects the HDL-C levels, although HDL-C was reduced by LPS injection in control wild type mice. Thus, upregulation of EL may account for the reduced HDL-C in systemic inflammation. Taken together presence of EL and regulated expression of EL may have unique functional roles in the pathogenesis of coronary artery diseases such as atherosclerosis as well as in lipid metabolism in the vessel wall. Therefore, EL is considered to be an attractive therapeutic target for pharmacological intervention to raising HDL-C and to prevent atherosclerosis.
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Report
(3 results)
Research Products
(21 results)
