Studies on the initiation and regression of atherosclerosis

动脉粥样硬化发生和消退的研究

• 批准号: 05044163
• 负责人: KITA Toru
• 金额: $ 6.4万
• 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: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1994
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-05044163/
• 关键词: familial hypercholesterolemia atherosclerosis; VCAM-1; WHHL-rabbit; lysophosphatidyl-choline; oxidized LDL; ICAM-1; T lymphocyte; Tリンパ球; 粥状動脈硬化; 血管内皮細胞; Cキナーゼ

Using a new animal model for endogenous hypercholesterolemia, named Watanabe-heritable-hyperlipidemic rabbit, which has a severe fulminant atherosclerosis, we have investigated the sequential expression of monocyteadhesion molecule (VCAM-1), macrophages and T lymphocytes in and on the endothelial monolinear before and after the atherosclerotic lesions covered the space by anti-VCAM-1, macrophage and T lymphocyte antibody respectively. Because our experimental purpose is sequential analysis what is going on the arterial wall in WHHL-rabbit, we chose the place where we examined the expression and existence VCAM-1, macrophage and T lymphocyte, that is the orifice of first branch of intercostal artery. At one month of age WHHL-rabbit, expression of VCAM-1 molecules is observed at the orifice of intercostal artery and covered around the wall at 2 month of age. In addition, at that time, monocytes started to accumulate in the arterial wall, named intimal legion. Three to four weeks later of … More this phenomenon T lymphocytes are observed in the same intimal space. In 1987, we reported that antioxidant, probucol, suppressed the progression of atherosclerotic legions in WHHL-rabbit. In 1991, we reported that in the atherosclerotic legions in probucol treated group there were few macrophage derived foam cells than untreated group. to explain these phenomenon we are thinking the possibility which probucol somehow inhibits the expression of VCAM-1 expression in the endothelial cells and this possibility is now under examined. The mechanism why VCAM-1 is induced on the endothelial cell in WHHL rabbit is under investigated in vitro and ICAM-1, another monocyte adhesion molecule, is also examined. Lysophosphatidylcholine (Lyso-PC) which generated in atherosclerotic lesions, has been shown to differentially up regulate VCAM-1 and ICAM-1 expression in various cultured endothelial cells. In case of ICAM-1, induction of this molecules is independent of PMA-regulatable PKC activation but suppressed by increased level of intracellular cyclic AMP.Therefore we focus and put forward on the signal transduction system of Lyso-PC on the expression of ICAM-1 and VCAM-1 collaboration with both Drs. Chait and Gimbrone. Less

本实验采用一种新的内源性高胆固醇血症动物模型--Watanabe-heritable-hypercholesterolemic兔，观察了动脉粥样硬化病变覆盖血管壁前后单核细胞粘附分子（VCAM-1）、巨噬细胞和T淋巴细胞在内皮细胞单层上的表达。由于我们的实验目的是对WHHL兔的动脉壁进行动态分析，所以我们选择了检测VCAM-1、巨噬细胞和T淋巴细胞表达和存在的部位，即肋间动脉第一分支的开口。1月龄WHHL-兔肋间动脉口可见VCAM-1分子表达，2月龄VCAM-1分子覆盖于壁周。此外，此时单核细胞开始在动脉壁聚集，称为内膜军团。三到四周后， ...更多信息 在相同的内膜空间中观察到这种现象T淋巴细胞。1987年，我们报道了抗氧化剂普罗布考抑制WHHL兔动脉粥样硬化的进展。1991年，我们报道普罗布考治疗组动脉粥样硬化斑块中巨噬细胞源性泡沫细胞较未治疗组少。为了解释这些现象，我们考虑普罗布考以某种方式抑制内皮细胞中VCAM-1表达的可能性，这种可能性现在正在研究中。本实验在体外研究了WHHL兔血管内皮细胞VCAM-1的诱导机制，并对另一种单核细胞粘附分子ICAM-1进行了检测。溶血磷脂酰胆碱（Lyso-PC）是动脉粥样硬化病变中产生的一种物质，它能不同程度地上调多种培养的内皮细胞中VCAM-1和ICAM-1的表达。在ICAM-1的情况下，这种分子的诱导不依赖于PMA可调节的PKC激活，但被细胞内cAMP水平的增加所抑制。因此，我们与Chait和Gimbrone博士合作，重点提出了Lyso-PC对ICAM-1和VCAM-1表达的信号转导系统。少

项目成果

Makoto Tanaka,et al.: "Regulation of apolipoprotein B production and secretion in response to the change of intracellular cholesteryl ester contents in rabbit hepatocytes." J.Biol.Cehm.268. 907-911 (1993)

Makoto Tanaka 等人：“根据兔肝细胞内胆固醇酯含量的变化调节载脂蛋白 B 的产生和分泌。”

Noriaki Kume,et al.: "Lysophosphatidylcholine transcriptionally induces growth factor gene expression in cultured human endothelial cells." J.Clin.Invest.93. 907-911 (1993)

Noriaki Kume 等人：“溶血磷脂酰胆碱在培养的人内皮细胞中转录诱导生长因子基因表达。”

Yasuhiro Hakamata,et al.: "Involvement of the brain type of ryanodine receptor in T-cell proliferation." FEBS Lett. 352. 206-210 (1994)

Yasuhiro Hakamata 等人：“脑型兰尼碱受体参与 T 细胞增殖。”

Makoto Tanaka,et al.: "Regulation of apolipoprotein B secretion in hepatocytes from Watanabe heritable hyperlipidemic rabbit,an animal model of familial hypercholesterolemia." Atherosclerosis. in press.

Makoto Tanaka 等人：“渡边遗传性高脂血症兔（一种家族性高胆固醇血症动物模型）肝细胞中载脂蛋白 B 分泌的调节”。

Makoto Tanaka, et al.: "Regulation of apolipoprotein B production and secretion in response to the change of intracellular cholesteryl ester contents in rabbit hepatocytes." J.Biol.Chem.268. 12713-12718 (1993)

Makoto Tanaka 等人：“根据兔肝细胞内胆固醇酯含量的变化调节载脂蛋白 B 的产生和分泌。”