BP.06.01] THE EFFECTS OF FEBUXOSTAT ON ANGIOTENSIN II-INDUCED VASCULAR REMODELING

Abstract

Objective: A xanthine oxidase (XO) inhibitor, febuxostat (FEB) is often used in patients with hyperuricemia. Several reports have suggested that uric acid contributes to endothelial dysfunction and kidney injury. Because XO produces hydrogen peroxide with uric acid in the nucleic acid metabolism, XO inhibitors can also have the anti-oxidative properties. From these reasons, XO inhibitors have the possibilities to suppress cardiovascular diseases. Actually, the effects of FEB on cardiovascular events have been examined in several clinical trials in Japan and several basic researches have suggested that FEB suppressed cardiac fibrosis and renal inflammation, however, those mechanisms remain unclear. In this study, we investigated the effects of FEB on angiotensin II (Ang II)-induced vascular remodeling. Design and method: To induce vascular remodeling, Ang II (2 mg/kg/day, s.c.) was infused by osmotic minipump into the mice. FEB was suspended in 1% carboxymethyl cellulose and administrated daily for 14 days. The mice were divided into four groups: control, FEB alone, Ang II alone, and Ang II+FEB. Medial thickening and vascular fibrosis were assessed by Elastica van Gieson stain. Blood pressure was measured by tail-cuff method. The macrophage infiltration and XO localization in the aortic tissue were assessed by immunofluorescence. In our in vitro studies, protein phosphorylation and cell proliferation were measured by western blotting and MTT assay, respectively. Results: Serum XO activity was lower in the Ang II+FEB group than in the Ang II alone group. FEB administration suppressed Ang II-induced blood pressure elevation and aortic fibrosis, however it did not affect medial thickening of the aortae. In our in vitro studies, FEB did not change the aortic smooth muscle cell proliferation and ERK1/2 phosphorylation induced by Ang II stimulation. We found that XO was expressed strongly in the macrophages, and Ang II-induced macrophage infiltration in the aortae tended to be suppressed by FEB. Conclusions: Our results suggested that FEB affects the mechanisms of fibrosis in vascular cells more than those of smooth muscle cell proliferation induced by Ang II. We supposed that FEB suppresses macrophage-derived XO activity in the mouse model of Ang II-induced vascular remodeling.