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

53 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 1 2012

Fingerprint

Xanthine Dehydrogenase
Foam Cells
Atherosclerosis
Macrophages
Allopurinol
Gene Knockdown Techniques
Hyperuricemia
VLDL Lipoproteins
Apolipoproteins E
Knockout Mice
Small Interfering RNA
Oral Administration
Aorta

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

Xanthine oxidoreductase is involved in macrophage foam cell formation and atherosclerosis development. / Kushiyama, Akifumi; Okubo, Hirofumi; Sakoda, Hideyuki; Kikuchi, Takako; Fujishiro, Midori; Sato, Hirokazu; Kushiyama, Sakura; Iwashita, Misaki; Nishimura, Fusanori; Fukushima, Toshiaki; Nakatsu, Yusuke; Kamata, Hideaki; Kawazu, Shoji; Higashi, Yukihito; Kurihara, Hiroki; Asano, Tomoichiro.

In: Arteriosclerosis, thrombosis, and vascular biology, Vol. 32, No. 2, 01.02.2012, p. 291-298.

Research output: Contribution to journalArticle

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, vol. 32, no. 2, pp. 291-298. https://doi.org/10.1161/ATVBAHA.111.234559
Kushiyama, Akifumi ; Okubo, Hirofumi ; Sakoda, Hideyuki ; Kikuchi, Takako ; Fujishiro, Midori ; Sato, Hirokazu ; Kushiyama, Sakura ; Iwashita, Misaki ; Nishimura, Fusanori ; Fukushima, Toshiaki ; Nakatsu, Yusuke ; Kamata, Hideaki ; Kawazu, Shoji ; Higashi, Yukihito ; Kurihara, Hiroki ; Asano, Tomoichiro. / Xanthine oxidoreductase is involved in macrophage foam cell formation and atherosclerosis development. In: Arteriosclerosis, thrombosis, and vascular biology. 2012 ; Vol. 32, No. 2. pp. 291-298.
@article{0ad371eb0171443194edfdbc7ffbd4d4,
title = "Xanthine oxidoreductase is involved in macrophage foam cell formation and atherosclerosis development",
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.",
author = "Akifumi Kushiyama and Hirofumi Okubo and Hideyuki Sakoda and Takako Kikuchi and Midori Fujishiro and Hirokazu Sato and Sakura Kushiyama and Misaki Iwashita and Fusanori Nishimura and Toshiaki Fukushima and Yusuke Nakatsu and Hideaki Kamata and Shoji Kawazu and Yukihito Higashi and Hiroki Kurihara and Tomoichiro Asano",
year = "2012",
month = "2",
day = "1",
doi = "10.1161/ATVBAHA.111.234559",
language = "English",
volume = "32",
pages = "291--298",
journal = "Arteriosclerosis, Thrombosis, and Vascular Biology",
issn = "1079-5642",
publisher = "Lippincott Williams and Wilkins",
number = "2",

}

TY - JOUR

T1 - Xanthine oxidoreductase is involved in macrophage foam cell formation and atherosclerosis development

AU - Kushiyama, Akifumi

AU - Okubo, Hirofumi

AU - Sakoda, Hideyuki

AU - Kikuchi, Takako

AU - Fujishiro, Midori

AU - Sato, Hirokazu

AU - Kushiyama, Sakura

AU - Iwashita, Misaki

AU - Nishimura, Fusanori

AU - Fukushima, Toshiaki

AU - Nakatsu, Yusuke

AU - Kamata, Hideaki

AU - Kawazu, Shoji

AU - Higashi, Yukihito

AU - Kurihara, Hiroki

AU - Asano, Tomoichiro

PY - 2012/2/1

Y1 - 2012/2/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84856228005&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84856228005&partnerID=8YFLogxK

U2 - 10.1161/ATVBAHA.111.234559

DO - 10.1161/ATVBAHA.111.234559

M3 - Article

C2 - 22095983

AN - SCOPUS:84856228005

VL - 32

SP - 291

EP - 298

JO - Arteriosclerosis, Thrombosis, and Vascular Biology

JF - Arteriosclerosis, Thrombosis, and Vascular Biology

SN - 1079-5642

IS - 2

ER -