Molecular mechanism on the progression of atherosclerosis.

动脉粥样硬化进展的分子机制。

• 批准号: 07044255
• 负责人: KITA Toru
• 金额: $ 5.63万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for international Scientific Research
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07044255/
• 关键词: Oxidized LDL; WHHL-rabbit; Lysophosphatidyl-choline; T-lymphocytes; Adhesion molecule; Smooth muscle growth factor; Atherosclerosis; Macrophages; INF-gamma; P selectin; HB‐EGF; PDGF; INF‐γ; IL‐2受容体

We are focussing on the atherogenesity of oxidized LDL,in particular lysophosphatidyl-choline (Lyso-PC) which generated in atherosclerotic lesions. Lyso-PC has been shown to differentially up regulate adhesion molecules, such as VCAM-1 and ICAM-1 expression and growth factors in various cultured cells, including endothelial cells, macrophages and T cells. In addition, INF-gamma and IL-2 receptor are induced by Lyso-PC in T cells.In case of PDGF-B chain and ICAM-1, induction of these molecules are independent of PMA-regulatable PKC activation but suppressed by increased level of intracellular cyclic AMP in cultured endothelial cells. In addition, induction of PDGF-B chain is required newly synthesized protein, probably transcriptional factor. Therefore we put forward on the signal transduction system of Lyso-PC,concerning the expression of ICAM-1 and PDGF-B chain collaboration with both Dr.Chait, Cybulsky and Gimbrone.We also investigated the sequential expression of P-selectin, VCAM-1, E-selectin, activated macrophages and T lymphocytes in and on the endothelial cellsby antibodies respectively, using cholesterol fed rabbits at the orifice of first branch of intercostal artery. At one week of cholesterol feeding, P-selectin and VCAM-1 are detected. And activated macrophages are observed in the same place at following 2 weeks. At three week after cholesterol-feeding, T-lymphocytes are detected at the same place and continued to be detected until 10 weeks. However E-selectin was not detected.

我们的重点是氧化LDL的动脉粥样硬化，特别是在动脉粥样硬化病变中产生的溶血磷脂酰胆碱（Lyso-PC）。Lyso-PC在内皮细胞、巨噬细胞和T细胞等多种培养细胞中，可差异性上调VCAM-1、ICAM-1等粘附分子和生长因子的表达。此外，Lyso-PC还能诱导T细胞中inf - γ和IL-2受体的表达。在PDGF-B链和ICAM-1的情况下，这些分子的诱导不依赖于pma可调节的PKC激活，但在培养的内皮细胞中被细胞内环AMP水平的增加所抑制。另外，诱导PDGF-B链需要新合成的蛋白，可能是转录因子。因此我们与Dr.Chait， Cybulsky和Gimbrone合作，提出了Lyso-PC的信号转导系统，涉及ICAM-1和PDGF-B链的表达。我们用胆固醇喂养的家兔肋间动脉第一分支口分别用抗体序贯表达p -选择素、VCAM-1、e -选择素、活化巨噬细胞和T淋巴细胞。在给药一周时检测p -选择素和VCAM-1。2周后在同一部位观察活化的巨噬细胞。给胆固醇后3周，在同一部位检测t淋巴细胞，并持续检测至10周。但未检测到E-selectin。

项目成果

Uematsu-Yanagita,M.et al.: "Microscopic polyarteritis during polymyaliga rtheumatica remission." Am.J.Kid.Dis.28. 289-291 (1996)

Uematsu-Yanagita,M.et al.：“风湿性多肌炎缓解期间的显微镜下多动脉炎。”

Ochi,H.et al.: "Elevated levels of cyclic AMP inhibits protein kinase-C independent mechanisms of endothelial PDGF-B chain and ICAM-1 gene induction by lysophosphatidyl choline." Circulation Research. 77. 530-535 (1995)

Ochi, H. 等人：“环 AMP 水平升高会抑制溶血磷脂酰胆碱诱导内皮 PDGF-B 链和 ICAM-1 基因诱导的蛋白激酶 C 独立机制。”

Kita,T.et al.: "Induction of endothelial platelet-derived growth factor-b-chain and intercellular adhesion molecule-1 by lysophosphatidylcholine" The Ann.N.Y.Acad.Sci.(in press).

Kita,T.等人：“溶血磷脂酰胆碱诱导内皮血小板衍生生长因子-b-链和细胞间粘附分子-1”，Ann.N.Y.Acad.Sci.（正在出版）。

Yokode,M.et al.: "Modification of high-and low-density lipoproteins by cigarette smoke oxidants." The Ann.N.Y.Acad.Sci.786. 245-251 (1996)

Yokode,M.等人：“香烟烟雾氧化剂对高密度脂蛋白和低密度脂蛋白的修饰。”

Kita,T.et al.: "Lessons concerning human lipoprotein metabolism from the study of the WHHL rabbit." Atherosclerosis. X. 111-113 (1995)

Kita,T.等人：“从 WHHL 兔子的研究中获得有关人类脂蛋白代谢的教训。”