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Uric acid lowering treatment alleviates perivascular carotid collar placement induced neointimal lesions in Uricase knockout mice

Jie Lu, Ming-Shu Sun, Xin-Jiang Wu, Xuan Yuan, Zhen Liu, Xiao-Jie Qu, Xiao-Peng Ji, Tony R Merriman, View ORCID ProfileChang-Gui Li
doi: https://doi.org/10.1101/366096
Jie Lu
1Institute of Metabolic Diseases, Qingdao University, Qingdao, China
2Shandong Provincial Key Laboratory of Metabolic Diseases and Qingdao Key Laboratory of Gout, the Affiliated Hospital of Qingdao University, Qingdao, China
3Department of Endocrinology and Metabolic Diseases, the Affiliated Hospital of Qingdao University, Qingdao, China
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Ming-Shu Sun
1Institute of Metabolic Diseases, Qingdao University, Qingdao, China
2Shandong Provincial Key Laboratory of Metabolic Diseases and Qingdao Key Laboratory of Gout, the Affiliated Hospital of Qingdao University, Qingdao, China
4Department of Rheumatology and Clinical Immunology, the Affiliated Hospital of Qingdao University, Qingdao, China
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Xin-Jiang Wu
1Institute of Metabolic Diseases, Qingdao University, Qingdao, China
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Xuan Yuan
1Institute of Metabolic Diseases, Qingdao University, Qingdao, China
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Zhen Liu
1Institute of Metabolic Diseases, Qingdao University, Qingdao, China
2Shandong Provincial Key Laboratory of Metabolic Diseases and Qingdao Key Laboratory of Gout, the Affiliated Hospital of Qingdao University, Qingdao, China
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Xiao-Jie Qu
1Institute of Metabolic Diseases, Qingdao University, Qingdao, China
2Shandong Provincial Key Laboratory of Metabolic Diseases and Qingdao Key Laboratory of Gout, the Affiliated Hospital of Qingdao University, Qingdao, China
3Department of Endocrinology and Metabolic Diseases, the Affiliated Hospital of Qingdao University, Qingdao, China
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Xiao-Peng Ji
1Institute of Metabolic Diseases, Qingdao University, Qingdao, China
2Shandong Provincial Key Laboratory of Metabolic Diseases and Qingdao Key Laboratory of Gout, the Affiliated Hospital of Qingdao University, Qingdao, China
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Tony R Merriman
5Department of Biochemistry, University of Otago, Dunedin, New Zealand
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Chang-Gui Li
1Institute of Metabolic Diseases, Qingdao University, Qingdao, China
2Shandong Provincial Key Laboratory of Metabolic Diseases and Qingdao Key Laboratory of Gout, the Affiliated Hospital of Qingdao University, Qingdao, China
3Department of Endocrinology and Metabolic Diseases, the Affiliated Hospital of Qingdao University, Qingdao, China
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  • ORCID record for Chang-Gui Li
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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 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. Mouse model of induced carotid atherosclerosis was established in the novel spontaneous HU Uox-KO mouse and their wild type littermates (C57BL/6J background). Mice were implanted with a perivascular collar placement around the right carotid artery in combination with a western-type diet. To investigate urate-lowering treatment (ULT) effects on intima, the mice were gavaged daily from the age of 6 weeks with allopurinol. Human umbilical vein endothelial cells (HUVECs) were co-incubated with soluble urate, with and without probenecid, to study the mechanism of urate-related atherosclerosis. The Uox-KO mice had significantly elevated serum urate levels combined with higher blood urea nitrogen and serum creatinine. Western blot analysis showed enhanced levels of atherosclerosis inflammatory response proteins. However, there were no other risk indicators for the pathogenesis of atherosclerosis, including increased fasting glucose, altered lipid and atherosclerosis characterized cardiovascular and histological manifestations. In contrast, collar placement Uox-KO mice 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 (P< 0.05). ULT alleviated atherosclerosis inflammatory response factors and reactive oxygen species intensities in both collar placement Uox-KO mice and urate-stimulated 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 mice. Urate worsens carotid neointimal lesions induced by the perivascular collar and urate-lowering therapy partially abrogates the effects. The current study warrants the further human based study on the possible benefits of urate-lowering therapy in atherosclerosis patients with HU.

Summary statement We generated a carotid collar placement atherosclerosis model in the novel spontaneous HU Uox-KO mouse and demonstrate that urate plays a contributing rather than a causal role in the carotid neointimal lesions, while urate-lowering treatment may bring additional benefits in this HU mouse model.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted July 10, 2018.
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Uric acid lowering treatment alleviates perivascular carotid collar placement induced neointimal lesions in Uricase knockout mice
Jie Lu, Ming-Shu Sun, Xin-Jiang Wu, Xuan Yuan, Zhen Liu, Xiao-Jie Qu, Xiao-Peng Ji, Tony R Merriman, Chang-Gui Li
bioRxiv 366096; doi: https://doi.org/10.1101/366096
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Uric acid lowering treatment alleviates perivascular carotid collar placement induced neointimal lesions in Uricase knockout mice
Jie Lu, Ming-Shu Sun, Xin-Jiang Wu, Xuan Yuan, Zhen Liu, Xiao-Jie Qu, Xiao-Peng Ji, Tony R Merriman, Chang-Gui Li
bioRxiv 366096; doi: https://doi.org/10.1101/366096

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