Xanthine Oxidase Inhibition by Febuxostat Attenuates Experimental Atherosclerosis in Mice

Abstract

Atherosclerosis is a chronic inflammatory disease due to lipid deposition in the arterial wall. Multiple mechanisms participate in the inflammatory process, including oxidative stress. Xanthine oxidase (XO) is a major source of reactive oxygen species (ROS) and has been linked to the pathogenesis of atherosclerosis, but the underlying mechanisms remain unclear. Here, we show enhanced XO expression in macrophages in the atherosclerotic plaque and in aortic endothelial cells in ApoE−/− mice, and that febuxostat, a highly potent XO inhibitor, suppressed plaque formation, reduced arterial ROS levels and improved endothelial dysfunction in ApoE−/− mice without affecting plasma cholesterol levels. In vitro, febuxostat inhibited cholesterol crystal-induced ROS formation and inflammatory cytokine release in murine macrophages. These results demonstrate that in the atherosclerotic plaque, XO-mediated ROS formation is pro-inflammatory and XO-inhibition by febuxostat is a potential therapy for atherosclerosis.

Linking uric acid metabolism to diabetic complications

“…XDH/XO knockdown or allopurinol administration inhibited foam cell formation in macrophage J774.1 cells. The production of inflammatory cytokines associated with foam cell formation was reduced by allopurinol and febuxostat, and these medications also significantly improved calcification and lipid accumulation in the aortic plaque of ApoE-KO mice [36,95] . It should be noted that the expression of XDH/XO and the deposition of UA are seen in macrophages in arteriosclerotic lesions [96] .…”

“…It should be noted that the expression of XDH/XO and the deposition of UA are seen in macrophages in arteriosclerotic lesions [96] . In vitro, febuxostat inhibited cholesterol crystalinduced ROS formation [95] . Some reports describe XDH/XO as an endogenous regulator of cyclooxygenase (Cox)-2 [97] in the inflammatory system, and XDH/XO is central to innate immune function [98] .…”

Impact of Serum Uric Acid Levels on Coronary Plaque Stability Evaluated Using Integrated Backscatter Intravascular Ultrasound in Patients with Coronary Artery Disease

“…Xanthine oxidoreductase (XOR), which is the rate-limiting enzyme of uric acid production, is reportedly expressed in macrophages 28) . Lipid accumulation in, and macrophage infiltration into, injured vascular endothelia are inhibited by XOR inhibitors 29,30) . Activated XOR may promote atherosclerotic plaque formation through lipid accumulation into the plaque.…”

Reactive Oxygen Species Generation and Atherosclerosis

“…XO inhibitors have been reported to inhibit macrophage ROS formation, inflammatory cytokine release, and atherosclerosis. [99][100][101] However, XO breaks down hypoxanthine and xanthine to uric acid and produces ROS, both of which may affect the function of macrophages. A recent report has elucidated that XO-dependent generation of ROS, rather than uric acid, mediates inflammatory cytokine production in macrophages.…”