Xanthine oxidoreductase is involved in macrophage foam cell formation and atherosclerosis development

Akifumi Kushiyama, Hirofumi Okubo, Hideyuki Sakoda, Takako Kikuchi, Midori Fujishiro, Hirokazu Sato, Sakura Kushiyama, Misaki Iwashita, Fusanori Nishimura, Toshiaki Fukushima, Yusuke Nakatsu, Hideaki Kamata, Shoji Kawazu, Yukihito Higashi, Hiroki Kurihara, Tomoichiro Asano

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)291-298
Number of pages8
JournalArteriosclerosis, thrombosis, and vascular biology
Volume32
Issue number2
DOIs
Publication statusPublished - Feb 2012

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

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    Kushiyama, A., Okubo, H., Sakoda, H., Kikuchi, T., Fujishiro, M., Sato, H., Kushiyama, S., Iwashita, M., Nishimura, F., Fukushima, T., Nakatsu, Y., Kamata, H., Kawazu, S., Higashi, Y., Kurihara, H., & Asano, T. (2012). Xanthine oxidoreductase is involved in macrophage foam cell formation and atherosclerosis development. Arteriosclerosis, thrombosis, and vascular biology, 32(2), 291-298. https://doi.org/10.1161/ATVBAHA.111.234559