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

动脉粥样硬化的发生发展是由动脉壁内皮细胞损伤引起的。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。这导致我们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。为了确定控制含载脂蛋白B的脂蛋白保留的因素，我们建立了突变小鼠系：APOBEC-1敲除小鼠，脂蛋白脂酶（LPL）转基因小鼠，载脂蛋白E转基因小鼠。通过破坏APOBEC-1基因消除Apo B-48。我们进一步将这些动物与低密度脂蛋白受体（LDLR）基因敲除小鼠和载脂蛋白E基因敲除小鼠杂交，并检查动脉粥样硬化。在有和没有载脂蛋白B-48的小鼠之间，主动脉病变的大小没有差异，表明载脂蛋白B-100的致动脉粥样硬化潜力与载脂蛋白B-48相似。在载脂蛋白E缺乏的情况下，LPL过表达减少了动脉粥样硬化病变的大小。由于这种作用不伴随血浆载脂蛋白B水平的变化，因此脂蛋白上的LPL直接参与动脉粥样硬化性脂蛋白滞留的减少是合理的。同样，载脂蛋白E过表达降低了LDLR缺乏时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，载脂蛋白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可能作为载脂蛋白B-脂蛋白的动脉滞留的调节剂。载脂蛋白B亚型和载脂蛋白E似乎没有这种功能。

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.