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.
Highlights
Atherosclerosis is a chronic inflammatory disease due to lipid deposition in the arterial wall
In aortic sinus from ApoE2/2 mice, xanthine oxidoreductase (XOR) protein was abundantly expressed in MOMA-2-positive macrophages infiltrated into the plaque, whereas it was very low in nonatherosclerotic aortic sinus from WT mice
As macrophages and endothelial cells are involved in the process of plaque formation and endothelial dysfunction, we hypothesized that XOR could play a role in both these pathogenic processes of atherosclerosis
Summary
Atherosclerosis is a chronic inflammatory disease due to lipid deposition in the arterial wall. Febuxostat inhibited cholesterol crystal-induced ROS formation and inflammatory cytokine release in murine macrophages. ROS scavengers such as N-acetyl-L-cysteine (NAC) and apocynin inhibited plaque formation and arterial inflammation in mice[12,13,14] These findings strongly suggest that XO plays an important role in the progression of atherosclerosis through ROS generation but definitive proof of its role in atherosclerotic inflammation and the underlying mechanisms remain to be established. Intracellular ROS production has been shown to be critical for the NLRP3-dependent secretion of IL-1b in response to monosodium urate (MSU)[18,19] It is not known if CC-induced pro-inflammatory cytokine release is a XO- or ROS-dependent process. We examined the expression of XO in experimental atherosclerosis, and studied the effects of febuxostat, a highly potent inhibitor of XOR, both in vivo in the atherosclerosis model and in vitro in CC-induced inflammation in macrophages
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