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Study on the role of arterial retention of lipoprotein and its regulators in the development of atheroselerosis

动脉脂蛋白潴留及其调节因子在动脉粥样硬化发生发展中的作用研究

基本信息

批准号：
09470217
负责人：
ISHIBASHI Syun
金额：
$ 8.51万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

项目摘要

It has been widely accepted that development of atherosclerosis is initiated by response to injury of endothelium in arterial wall. However, no evidence of the endothelial injury was found in certain animal models of atherosclerosis associated with hyperlipoproteinemia. This lead us to the hypothesis that atherosclerosis is triggered by retention of atherogenic lipoproteins in the arterila wall. To identify factors which govern retention of apo B-containing lipoproteins, we have established lines of mutant mice : APOBEC-1 knockout mice, lipoprotein lipase (LPL) trasgenic mice, apo E trasgenic mice. Apo B-48 is eliminated by the disruption of APOBEC-1 gene. We further cross-bred these animals to the low density lipoprotein receptor (LDLR) knockout mice and apo E knockout mice and examined the atherosclerosis. There was no difference in the size of aortic lesions between mice with and without apo B-48, indicating that the atherogenic potential of apo B-100 is similar to that of apo B-48. LPL overexpression reduced atherosclerotic lesion size in the setting of the apo E deficiency. Since this effect was not accompanied by the changes in the plasma apo B levels, it is plausible that LPL on the lipoproteins is directly involved in the reduction of the arterial retention of atherogenic lipoproteins. Similarly, apo E overexpression reduced atherosclerotic lesion size in the setting of the LDLR deficiency. In this case, the changes in the plaque size were parallel to those of the plasma apo B levels. Therefore, it is unlikely that apo E regulates directly the arterial retention of atherogenic lipoproteins. In conclusion, LPL may function as a regulator of arterial retention of apo B-containing lipoproteins. Apo B isoforms and apo E do not appear to have this function.

人们普遍认为，动脉粥样硬化的发展是由动脉壁内皮损伤的反应引发的。然而，在某些与高脂蛋白血症相关的动脉粥样硬化动物模型中，没有发现内皮损伤的证据。这使我们得出这样的假设：动脉粥样硬化是由动脉壁中致动脉粥样硬化脂蛋白的滞留引发的。为了确定控制含apo B脂蛋白保留的因素，我们建立了突变小鼠系：APOBEC-1敲除小鼠、脂蛋白脂肪酶(LPL)转基因小鼠、apo E转基因小鼠。 Apo B-48 通过破坏 APOBEC-1 基因而被消除。我们进一步将这些动物与低密度脂蛋白受体（LDLR）敲除小鼠和apo E敲除小鼠杂交，并检查动脉粥样硬化。有和没有apo B-48的小鼠之间主动脉病变的大小没有差异，表明apo B-100的致动脉粥样硬化潜力与apo B-48相似。在 apo E 缺乏的情况下，LPL 过度表达可减少动脉粥样硬化病变的大小。由于这种效应并不伴随血浆载脂蛋白 B 水平的变化，因此脂蛋白上的 LPL 可能直接参与减少致动脉粥样硬化脂蛋白的动脉滞留。同样，在 LDLR 缺乏的情况下，apo E 过度表达可减少动脉粥样硬化病变的大小。在这种情况下，斑块大小的变化与血浆载脂蛋白 B 水平的变化平行。因此，apo E 不太可能直接调节致动脉粥样硬化脂蛋白的动脉滞留。总之，LPL 可能起到调节含 apo B 脂蛋白动脉滞留的作用。 Apo B 同工型和 apo E 似乎不具有此功能。