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.

Harnessing hyperuricemia to atherosclerosis and understanding its mechanistic dependence

“…Allopurinol also reduced the oxidative stress level and inflammatory cytokines significantly. Hence, these results could benefit atherosclerotic patients with hyperuricemia 58 …”

Uric Acid and Cardiovascular Disease: An Update From Molecular Mechanism to Clinical Perspective

“…Endothelial dysfunction plays a critical role in the development and progression of atherosclerosis, leading to serious cardiovascular events. Experimental studies show that high UA aggravates the inflammation response and oxidative stress and, thus, leads to endothelial dysfunction ( Xiao et al, 2015 ; Johnson et al, 2018 ; Li et al, 2018 ; Lu et al, 2019 ). Additionally, hyperuricemia-induced endothelial dysfunction is also confirmed in many clinical studies ( Mercuro et al, 2004 ; Kato et al, 2005 ; Ho et al, 2010 ; Tomiyama et al, 2011 ; Sincer et al, 2014 ).…”

“…Recent epidemiological studies show that hyperuricemia may be involved in hypertension, diabetes, atherosclerosis, chronic kidney disease, and atrial fibrillation (AF) as well as the occurrence of cardiovascular events ( Kuwabara et al, 2017a ; Kuwabara et al, 2017b ; Kuwabara et al, 2017c ; Kuwabara et al, 2018a ; Kuwabara et al, 2018b ; Maruhashi et al, 2018 ). Experimental studies show that hyperuricemia promotes the occurrence and development of cardiovascular diseases by regulating molecular signals, such as inflammatory response ( Xiao et al, 2015 ; Johnson et al, 2018 ; Lu et al, 2019 ), oxidative stress ( Li et al, 2018 ), insulin resistance ( Zhi et al, 2016 ), endothelial dysfunction ( Maruhashi et al, 2018 ), and endoplasmic reticulum stress ( Li P. et al, 2016 ; Yan et al, 2018 ).…”

Phagocytosis of Polymeric Nanoparticles Aided Activation of Macrophages to Induce Atherosclerotic Plaques in Apoe-/- Mice 

“…Internal environmental stability is based on the dynamic balance between in ammatory and anti-in ammatory responses. When the in ammatory response dominates, tissues and cells will be damaged; whereas, a strong anti-in ammatory reaction will inhibit immune function [39] . We initially determined that PLGA nanoparticles enter the body as foreign objects, triggering an in ammatory response in ApoE −/− mice.…”