Study for the pathogenesis of atherosclerosis.

经过多个不同领域的研究人员的共同努力，我们得到了以下结果：1)我们证实了氧化低密度脂蛋白在WHHL-兔动脉粥样硬化病变中的存在(动脉硬化和血栓形成1991)。2)我们已经证明了氧化低密度脂蛋白促进巨噬细胞产生和分泌PGE_2。然而，在这个项目中，我们发现巨噬细胞一旦被氧化的低密度脂蛋白变成泡沫细胞，就不再能产生前列腺素E_2。(提交)3)我们发现长期喂养抗氧化剂普罗布考可以通过抑制氧化的低密度脂蛋白的形成而阻止WHHL-兔动脉粥样硬化的形成。此外，普罗布考还能逆转WHHL兔的动脉粥样硬化病变。4)我们发现普罗布考能增强巨噬细胞的趋化作用。这可能解释了普罗布考的抗动脉粥样硬化作用(动脉硬化和血栓形成，1992)。…基因的分离和克隆更多或前列腺素E受体(J.Biol.化学。6)山田博士等人。结果表明，人重组巨噬细胞集落刺激因子(M-CSF)在酶活性和mRNA水平的基础上促进脂蛋白脂肪酶的产生和分泌。山田博士还通过DNA序列分析证实了五名患有家族性LPL缺乏症的无关日本患者的基因异常(明显的点突变)(动脉硬化和血栓形成，JCI 1991)。7)齐藤博士展示了从培养的平滑肌细胞中分离出的新的平滑肌细胞生长因子和迁移因子。8)山本博士在WHHL兔的病变中发现了转移mRNA的表达，但在对照兔中没有发现。他现在正在研究它的生物学意义(手稿准备)。9)我们证明了一旦高密度脂蛋白颗粒被氧化(被氧化的高密度脂蛋白)，不再被氧化的高密度脂蛋白可以促进胆固醇从泡沫细胞中流出(PNAS 1991)。Horiuchi博士用生化方法证明了巨噬细胞的内吞作用和随后的高密度脂蛋白的释放(BBA 1991)。较少

As a result of collaborating work among several researches from different fields, we could get following results ;1) We demonstrated the existence of oxidized LDL in the lesion of atherosclerosis from WHHL-rabbits (Arteriosclerosis and Thrombosis 1991).2) We have already showed that oxidized LDL enhances the production and secretion of PGE2 from macrophages. However in this project, we found that once macrophages become foam cells by oxidized LDL, no longer they could produce PGE_2. (submit)3) We discovered that long term feeding of probucol, an antioxidant, could prevent the progression of atheromatous formation in WHHL-rabbits as a result of inhibition of oxidized LDL formation. In addition, probucol could regress the atheromatous lesionsin WHHL rabbits (Atherosclerosis 1992).4) We showed that probucol enhanced the chemotaxis of macrophages. It might explain the probucol antiatherogenic effects (Arteriosclerosis and Thrombosis 1992).5) Dr. Narumiya et al. isolated and cloned a cDNA f … More or prostaglandin E receptor (J. Biol. Chem. in press).6) Dr. Yamada et al. showed that human recombinant macrophage-colony stimulating factor (M-CSF) enhanced lipoprotein lipase production and secretion on the basis of both enzyme activity and mRNA level. Dr. Yamada also demonstrated the gene abnormality (distinct point mutations) of five unrelated Japanese patients with familial LPL deficiency by DNA sequence analysis (Arteriosclerosis and Thrombosis 1991, JCI 1991).7) Dr. Saito demonstrated the new smooth muscle cell growth factor and migration factor from cultured smooth muscle cells. Now he is characterizing its property (Atherosclerosis 1991, Acta Medica et Biologica 1991).8) Dr. Yamamoto found the expression of transfering mRNA in WHHL-rabbit's lesions, but not in control rabbits. He is now studying its biological meaning (manuscript preparation).9) We demonstrated once HDL particles are oxidized (oxidized HDL), no longer oxidized HDL could promote the cholesterol efflux from foam cells (PNAS 1991). Dr. Horiuchi demonstrated biochemically that the endocytosis and subsequent resecretion of HDL in macrophages (BBA 1991). Less