Xanthine Oxidoreductase Is Involved in Macrophage Foam Cell Formation and Atherosclerosis Development
Xanthine Oxidoreductase Is Involved in Macrophage Foam Cell Formation and Atherosclerosis Development
复制标题
DOI：
10.1161/atvbaha.111.234559
复制
发表时间：
2012-02-01
影响因子：
8.7
通讯作者：
Asano, Tomoichiro
中科院分区：
文献类型：
--
作者：
Kushiyama, Akifumi;Okubo, Hirofumi;Asano, Tomoichiro
高尿酸血症在代谢综合征患者中很常见。我们研究了黄嘌呤氧化还原酶（XOR）在动脉粥样硬化的发展中的作用，和XOR抑制剂别嘌呤醇对这个process.Methods和Results-Oral给药的别嘌呤醇ApoE基因敲除小鼠显着改善主动脉和主动脉根部的脂质积累和钙化的影响。此外，别嘌呤醇处理或siRNA介导的XOR基因敲低抑制了用乙酰化LDL或极低密度脂蛋白（VLDL）处理的J774.1小鼠巨噬细胞转化为泡沫细胞。在原代培养的人巨噬细胞中也观察到别嘌呤醇的这种抑制作用。相反，XOR的过表达促进了J774.1细胞向泡沫细胞的转化。有趣的是，SR-A1，SR-B1，SR-B II和VLDL受体在J774.1细胞中通过XOR敲低而减少，并且通过XOR过表达而增加。相反，ABCA 1和ABCG 1的表达因XOR敲低而增加，并因XOR过表达而受到抑制。最后，伴随着泡沫细胞形成的炎性细胞因子的生产也减少了别嘌呤醇administration. Conclusion这些结果强烈建议XOR活动和/或其表达水平，以促进巨噬细胞泡沫细胞的形成。因此，XOR抑制剂可用于预防动脉粥样硬化。（Arterioscler Thromb Vasc Biol.2012;32：291-298.）
Objective-Hyperuricemia is common in patients with metabolic syndrome. We investigated the role of xanthine oxidoreductase (XOR) in atherosclerosis development, and the effects of the XOR inhibitor allopurinol on this process.Methods and Results-Oral administration of allopurinol to ApoE knockout mice markedly ameliorated lipid accumulation and calcification in the aorta and aortic root. In addition, allopurinol treatment or siRNA-mediated gene knockdown of XOR suppressed transformation of J774.1 murine macrophage cells, treated with acetylated LDL or very low density lipoprotein (VLDL) into foam cells. This inhibitory effect of allopurinol was also observed in primary cultured human macrophages. In contrast, overexpression of XOR promoted transformation of J774.1 cells into foam cells. Interestingly, SR-A1, SR-B1, SR-B II, and VLDL receptors in J774.1 cells were reduced by XOR knockdown, and increased by XOR overexpression. Conversely, expressions of ABCA1 and ABCG1 were increased by XOR knockdown and suppressed by XOR overexpression. Finally, productions of inflammatory cytokines accompanied by foam cell formation were also reduced by allopurinol administration.Conclusion-These results strongly suggest XOR activity and/or its expression level to contribute to macrophage foam cell formation. Thus, XOR inhibitors may be useful for preventing atherosclerosis. (Arterioscler Thromb Vasc Biol. 2012;32:291-298.)