Study for the initial event of athcrosclerosis.

动物研究显示动脉粥样硬化的初始特征之一是循环单核细胞迁移到内皮下空间并发展成巨噬细胞。巨噬细胞将脂蛋白整合到细胞体中，并转化为富含脂质的泡沫细胞，这是动脉粥样硬化早期的特征。然而，巨噬细胞只有少量的经典低密度脂蛋白（LDL）受体，并且以极低的速率吸收天然LDL，这不足以在体外引起泡沫细胞的形成。因此，研究人员对巨噬细胞中脂蛋白的掺入和代谢的其他机制非常感兴趣。据报道，这些细胞可以通过< β >-VLDL受体有效地吸收来自Watanabe遗传性高脂血症兔（一种家族性高胆固醇血症动物模型）的< β >-VLDL和VLDL。此外，巨噬细胞也被证明含有某些类型的化学修饰LDL。这种途径最初是在乙酰- ldl中发现的，其受体被称为乙酰- ldl受体。尽管这种受体的发现似乎解释了巨噬细胞异质形成的悖论，但在体内尚未发现一种自然发生的LDL修饰形式。据报道，最近氧化的LDL至少部分地被乙酰-LDL受体有效地被巨噬细胞吸收。由于病理和流行病学调查表明脂质过氧化与动脉粥样硬化有关，氧化LDL被认为是自然发生的修饰LDL的一个候选例子。虽然巨噬细胞泡沫细胞的形成被认为是动脉粥样硬化形成的关键事件之一，但它是否只是脂质细胞的积聚过程，还是对动脉粥样硬化的发展有一定的病理生理作用，目前还不清楚。巨噬细胞在被吞噬颗粒（如酶聚糖A）或炎症刺激（如脂多糖）激活时释放出各种生物活性物质，其中花生四烯酸代谢产物越来越受到人们的关注，最近的研究表明其与动脉粥样硬化密切相关。然而，在巨噬细胞和泡沫细胞形成过程中，受体介导的脂蛋白掺入过程中花生四烯酸酯的代谢却知之甚少。因此，对这一领域的研究是有价值的，因为它可能为我们确定有孔细胞的功能作用提供线索，以确定它们是否作为动脉粥样硬化形成的促进剂。在这项研究中，我们用脂蛋白培养小鼠腹腔巨噬细胞，并使用气相色谱-质谱联用和放射免疫分析法检测花生四烯酸酯代谢物的产生。我们报道氧化LDL在进入细胞的过程中刺激巨噬细胞的花生四烯酸代谢。少

One of the initial characteristics of atherosclerosis shown in animal studies is the migration of circulating monocytes into the subendothelial space and their development into macrophages. Macrophages incorporate lipoproteins into the cell body and get converted into lipid-laden foam cells, which are characteristically found in the early stage of atheroma. However, macrophages have only a few number of classical low density lipoprotein (LDL) receptor, and thke up native LDL at a very low rate, which is insufficient to cause foam cell formation in vitro. Therefors, investigators have been attracted to other mechanism of incorporation and metabolism of lipoproteins in macrophages. These cells have been reported to efficiently incorporate <beta>-VLDL and VLDL from Watanabe heritable hyperlipidemic rabbits, an animal model for familial hypercholesterolemia via a specific receptor, the <beta>-VLDL receptor. Moreover, macrophages were also demonstrated to incorporate certain types of chemic … More ally modified LDL. This pathway was first shown for acetyl-LDL and the receptor is called the acetyl-LDL receptor. Although the discovery of this receptor appeared to explain the paradox of macrophages in ahterogenesis, a naturally occurring modified form of LDL has not yet been identified in the body. Recently oxidized LDL has been reported to be efficiently taken up by macrophages at least in part by may of acetyl-LDL receptor. Because lipid peroxidation has been suggested to be involved in atherogenesis by pathological of epidemiological investigation, oxidized LDL is considered as a candidate for an example of naturally occurring, modified LDL.While foam cell formation of macrophages has been indicated to be one of the key events of atheroma formation, it has not been clarified yet whether it is only a process of accumulation of the lipid-laden cells or has some pathophysiological effects on the progression of atheroma. Macrophages release various biologically active substances when they are activated by phagocytic particles such as zymosan A or inflammatory stimuli such as lipopolysaccharideslAmong those substances, the products derived from arachidonate metabolism have attracted increasing attention, since recent studies have indicated their close relation to atherogensis. However, little is known yet about arachidonate metabolism during the process of receptor-mediated incorporation of lipoproteins by macrophages and foam cell formation. Studies on this lind, therefore, would be of some value, in as much as it might give us a clue for determining the functional role of the foram cells as to whether they act as a promotor for atheromatous formation.In this study, we incubated mouse peritoneal macrophages with lipoproteins and examined production of arachidonate metabolites with gas chromatography-mass spectrometry and redioimmunoassay. We report that oxidized LDL stimulates arachidonate metabolism in macrophages during its incorporation into the cells. Less