Urate-lowering therapy alleviates atherosclerosis inflammatory response factors and neointimal lesions in a mouse model of induced carotid atherosclerosis

Hyperuricemia (HU) is a cause of gout. Clinical studies show a link between HU and cardiovascular disease. However, the role of soluble serum urate (SU) on atherosclerosis development remains elusive. We aimed to use a new HU mouse model [Uricase/Uox knockout (KO)] to further investigate the relationship between HU and atherosclerosis. A mouse model by perivascular collar placement of induced carotid atherosclerosis was estab- lished in male Uox-KO mice. The Uox-KO mice had elevated SU levels and enhanced levels of atherosclerosis inflammatory response proteins. In con- trast, Uox-KO mice with carotid atherosclerosis showed severe neointimal changes in histology staining consistent with increases in intimal area and increases in proliferating cell nuclear antigen (PCNA)- and F4/80-positive cells. Allopurinol reduced neointimal areas induced by the perivascular collar in hyperuricemic mice, accompanied by decreased expression of PCNA- and F4/80-positive cells. Urate-lowering treatment alleviated atherosclerosis inflammatory response factors and reactive oxygen species (ROS) intensities in both collar placement Uox-KO mice and urate-stimulated human umbili- cal vein endothelial cells (HUVECs).In vitro results using HUVECs showed ROS was induced by urate and ROS induction was abrogated using antioxi- dants. These data demonstrate that urate per se does not trigger atheroscle- rosis intima lesions in male mice. Urate worsens carotid neointimal lesions induced by the perivascular collar and urate-lowering therapy partially abro- gates the effects. The current study warrants clinical studies on the possible benefits of urate-lowering therapy in atherosclerosis patients with HU.