1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
Arterioscler Thromb Vasc Biol. 2012 Feb;32(2):291-8. doi: 10.1161/ATVBAHA.111.234559. Epub 2011 Nov 17.
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.
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.
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.
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）在动脉粥样硬化发展中的作用，以及 XOR 抑制剂别嘌醇对这一过程的影响。
别嘌醇口服给予载脂蛋白 E 基因敲除小鼠，可明显改善主动脉和主动脉根部的脂质蓄积和钙化。此外，别嘌醇治疗或 siRNA 介导的 XOR 基因敲低可抑制乙酰化 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。这种别嘌醇的抑制作用也在原代培养的人巨噬细胞中观察到。相比之下，XOR 的过表达促进了 J774.1 细胞向泡沫细胞的转化。有趣的是，XOR 敲低降低了 J774.1 细胞中的 SR-A1、SR-B1、SR-B II 和 VLDL 受体，而 XOR 过表达则增加了这些受体。相反，XOR 敲低增加了 ABCA1 和 ABCG1 的表达，而 XOR 过表达则抑制了它们的表达。最后，泡沫细胞形成伴随的炎症细胞因子的产生也被别嘌醇给药所减少。
这些结果强烈表明 XOR 活性和/或其表达水平有助于巨噬细胞泡沫细胞的形成。因此，XOR 抑制剂可能有助于预防动脉粥样硬化。
