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

Abstract

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 established in male Uox-KO mice. The Uox-KO mice had elevated SU levels and enhanced levels of atherosclerosis inflammatory response proteins. In contrast, 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 umbilical vein endothelial cells (HUVECs). In vitro results using HUVECs showed ROS was induced by urate and ROS induction was abrogated using antioxidants. These data demonstrate that urate per se does not trigger atherosclerosis intima lesions in male mice. Urate worsens carotid neointimal lesions induced by the perivascular collar and urate-lowering therapy partially abrogates the effects. The current study warrants clinical studies on the possible benefits of urate-lowering therapy in atherosclerosis patients with HU.

• Authors: Jie Lu, Mingshu Sun, Xinjiang Wu, Xuan Yuan, Zhen Liu, Xiaojie Qu, Xiaopeng Ji, Tony R Merriman, Changgui Li
• Journal: The FEBS journal (FEBS J) Vol. 286 Issue 7 Pg. 1346-1359 (04 2019) ISSN: 1742-4658 [Electronic] England
• PMID: 30690853 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

Chemical References

• Antimetabolites
• Reactive Oxygen Species
• Uric Acid
• Allopurinol
• Urate Oxidase

Topics

• Allopurinol (pharmacology)
• Animals
• Antimetabolites (pharmacology)
• Carotid Artery Diseases (etiology, pathology, prevention & control)
• Human Umbilical Vein Endothelial Cells
• Humans
• Hyperuricemia (complications, physiopathology)
• Inflammation (etiology, pathology, prevention & control)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neointima (etiology, pathology, prevention & control)
• Reactive Oxygen Species (metabolism)
• Urate Oxidase (physiology)
• Uric Acid (metabolism)