Application of gene targeting to the study of atherosclerosis

为了阐明多种遗传因素在动脉粥样硬化过程中的作用，我们采用了小鼠发育生物学技术，特别是在ES细胞中利用同源重组进行基因打靶。我们建立了内皮素-1基因敲除小鼠、巨噬细胞清道夫受体基因敲除小鼠和其他基因靶向小鼠品系，以分析这些基因的作用，以及内皮细胞、平滑肌细胞和巨噬细胞参与动脉粥样硬化形成的机制。内皮素-1基因缺失的杂合子小鼠血压升高。从清道夫受体缺陷纯合子获得的巨噬细胞表明，乙酰化低密度脂蛋白的降解和氧化型低密度脂蛋白的降解均显著降低。此外，这些巨噬细胞还表明AGE和LPs的结合活性降低。这些基因在体内的功能与体外研究的不同，小鼠发育生物学技术，特别是基因打靶为分析这些问题提供了很好的工具。

In order to elucidate the role of multiple genetic factors on the process of atherosclerosis, we used the mouse developmental biological technics, especially gene targeting using homologous recombination in ES cells. We established the endothelin-1 knockout mice, macrophage scavenger receptor knockout mouse, and other gene targeted mice strains in order to analyze the roles of these genes, and the mechanism how endothelial cells, smooth muscle cells and macrophages are involved in the atherogenesis. The heterozygout mice deficient in endothekin-1 indicated the increase of blood pressure. Macrophage obtained from the homozygout for scavenger receptor deficiency indicated the marked decrease in both acetyl-LDL degradation and oxidized LDL degradation. Adding to this, these macrophage also indicated the decrease in the binding activity of both AGE and LPS.The function of these genes in vivo is different from those studied in vitro, and mouse developmental biological technics, especially gene targeting provide a nice tool to analyze these problems.