Xanthine Oxidase Inhibition by Febuxostat in Macrophages Suppresses Angiotensin II-Induced Aortic Fibrosis

Overview

Journal Am J Hypertens

Publisher Oxford University Press

Specialty Cardiology & Vascular Diseases

Date 2018 Oct 24

PMID 30351343

Citations 6

Authors

Masateru Kondo

Masaki Imanishi

Keijo Fukushima

Raiki Ikuto

Yoichi Murai

Yuya Horinouchi

Yuki Izawa-Ishizawa

Mitsuhiro Goda

Yoshito Zamami

Kenshi Takechi

Masayuki Chuma

Yasumasa Ikeda

Hiromichi Fujino

Koichiro Tsuchiya

Keisuke Ishizawa

Affiliations

Soon will be listed here.

Abstract

Background: Several reports from basic researches and clinical studies have suggested that xanthine oxidase (XO) inhibitors have suppressive effects on cardiovascular diseases. However, the roles of a XO inhibitor, febuxostat (FEB), in the pathogenesis of vascular remodeling and hypertension independent of the serum uric acid level remain unclear.

Methods: To induce vascular remodeling in mice, angiotensin II (Ang II) was infused for 2 weeks with a subcutaneously implanted osmotic minipump. FEB was administered every day during Ang II infusion. Aortic fibrosis was assessed by elastica van Gieson staining. Mouse macrophage RAW264.7 cells (RAW) and mouse embryonic fibroblasts were used for in vitro studies.

Results: FEB suppressed Ang II-induced blood pressure elevation and aortic fibrosis. Immunostaining showed that Ang II-induced macrophage infiltration in the aorta tended to be suppressed by FEB, and XO was mainly colocalized in macrophages, not in fibroblasts. Transforming growth factor-β1 (TGF-β1) mRNA expression was induced in the aorta in the Ang II alone group, but not in the Ang II + FEB group. Ang II induced α-smooth muscle actin-positive fibroblasts in the aortic wall, but FEB suppressed them. XO expression and activity were induced by Ang II stimulation alone but not by Ang II + FEB in RAW. FEB suppressed Ang II-induced TGF-β1 mRNA expression in RAW.

Conclusions: Our results suggested that FEB ameliorates Ang II-induced aortic fibrosis via suppressing macrophage-derived TGF-β1 expression.

Citing Articles

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TGF-β is elevated in hyperuricemic individuals and mediates urate-induced hyperinflammatory phenotype in human mononuclear cells.

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Mizuno Y, Yamamotoya T, Nakatsu Y, Ueda K, Matsunaga Y, Inoue M Int J Mol Sci. 2019; 20(19).

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Tao M, Pi X, Ma X, Shi Y, Zhang Y, Gu H BMJ Open. 2019; 9(3):e025453.

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