Xanthine Oxidase Inhibition by Febuxostat in Macrophages Suppresses Angiotensin II-Induced Aortic Fibrosis
Xanthine Oxidase Inhibition by Febuxostat in Macrophages Suppresses Angiotensin II-Induced Aortic Fibrosis
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DOI：
10.1093/ajh/hpy157
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发表时间：
2019-03-01
影响因子：
3.2
通讯作者：
Ishizawa, Keisuke
中科院分区：
文献类型：
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作者：
Kondo, Masateru;Imanishi, Masaki;Ishizawa, Keisuke
背景黄嘌呤氧化酶（XO）抑制剂对心血管疾病有抑制作用，已有基础研究和临床研究报道。然而，XO抑制剂，非布司他（FEB），在血管重塑和高血压的发病机制独立的血清尿酸level.Methods诱导血管重塑小鼠血管紧张素II（Ang II）的作用仍然不清楚2周皮下植入渗透微型泵。在Ang II输注期间每天给予FEB。通过弹性货车Gieson染色评估主动脉纤维化。结果FEB抑制血管紧张素Ⅱ诱导的血压升高和主动脉纤维化。免疫组化显示，血管紧张素II诱导的巨噬细胞浸润的主动脉往往被FEB抑制，XO主要是共定位在巨噬细胞，而不是在成纤维细胞。Ang II单独组主动脉中转化生长因子-1（TGF-1）mRNA表达被诱导，但Ang II + FEB组中未诱导。血管紧张素Ⅱ诱导平滑肌肌动蛋白阳性成纤维细胞在主动脉壁，但FEB抑制他们。XO的表达和活性诱导单独的Ang II刺激，但不是由Ang II + FEB在RAW。结论：FEB通过抑制巨噬细胞源性TGF-1的表达，减轻Ang Ⅱ诱导的主动脉纤维化。
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-1 (TGF-1) mRNA expression was induced in the aorta in the Ang II alone group, but not in the Ang II + FEB group. Ang II induced -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-1 mRNA expression in RAW.CONCLUSIONS Our results suggested that FEB ameliorates Ang II-induced aortic fibrosis via suppressing macrophage-derived TGF-1 expression.