Study On Atherosclerosis Induced By Hyperuricemia Via Vascular Endothelial Dysfunction

Background:Increased levels of serum uric acid(SUA)have been proposed as a risk factor for cardiovascular disease.However,the association between SUA and the prevalence of extracranial supra-aortic artery stenosis(SAAS),especially vertebral artery stenosis(VAS),is still unc Lear.The mechanism of atherosclerosis induced by hyperuricemia via vascular endothelial dysfunction is unclear,especially in dynamic fluidic status.Objective:We are aimed to investigate the incidence of hyperuricemia in asymptomatic people,the effect of serum uric acid on the extracranial supra-aortic artery stenosis and the different vascular susceptibility to hyperuricemia.Then we investigate the mechanism of uric acid on vascular endothelium dysfunction,monocytes adhesion,and the different vascular susceptibility under different hemodynamics in microfluidic system.Methods:1.This cross-sectional study included 3,325 asymptomatic Chinese individuals(1597males and 1728 females)aged 44–61 years old who were consecutively recruited from July 2013 to August 2014.Participants were classified into four groups according to SUA quartiles.A logistic regression model was used to estimate the odds ratios(OR)and 95% confidence intervals(95% CI)of SAAS prevalence in relation to SUA.SAAS was detected by vascular ultrasound.2.Human umbilical vein endothelial cells(HUVECs)were cultured in vitro.Cells were collected at different concentrations of uric acid(UA),and the cells were collected at different time points.The expression of(P)RR and NO / ET-1 were measured by western blot and m RNA expression.3.Different concentrations of UA stimulated HUVECs in vitro,and we detected the adhesion molecules of endothelial cells by western blot and m RNA expression.4.The microfluidic channel was designed to establish the microvascular flow model of blood vessels,and simulated the performance of different shear stress vessels under UA stimulation.5.The changes of(P)RR and ICAM-1 were observed in the microfluidic system,and the difference between the static and fluidic culture was compared.6.The adhesion effect of HUVECs and monocytes was observed by microfluidic technique in real time.Results:1.SUA levels ranged from 177.1 to 426.9 ?mol/L.Extracranial SAAS was detected in 24.2% of the participants(20.3% in the vertebral arteries,4.6% in the carotid arteries,and 0.9% in the subclavia arteries).2.After adjusting for confounders,SUA was independently associated with a higher risk of SAAS(OR: 1.375,95% CI: 1.033-1.830)in participants with the highest SUA quartile compared to participants with normal SUA.3.The adjusted OR for the prevalence of SAAS for each 100 ?mol/L increment in SUA was 1.132(95% CI: 1.006-1.275).The prevalence of VAS was independently associated with SUA in the highest quartile(OR: 1.439,95% CI:1.061-1.952).4.The expression of(P)RR was significantly increased after 9mg/dl uric acid stimulated HUVECs,compared with other groups.5.The expression of(P)RR increased at 12 th hour,reached the peak at 24 th hour after 9mg/dl UA stimulation,and decreased gradually after 36 hours which was still significantly higher than that of control group.The expression of(P)RR increased more significantly in the low shear stress than that in the static group.6.9mg/dl uric acid significantly increased m RNA of(P)RR,12mg/dl uric acid did not continue to increase m RNA of(P)RR.The level of(P)RR expression was positively correlated with uric acid below 9 mg/dl.7.The expression of ET-1 and eNOS didn't increase with the increasing concentration of uric acid,and the NO decreased with the increasing concentration.8.ICAM-1 expression increased with the increment of uric acid concentration.9mg/dl uric acid made ICAM-1 expression to the peak,6mg/dl and 12mg/dl UA also increased the expression of ICAM-1,but less than 9mg/dl UA.9 mg/dl UA significantly increased the m RNA of ICAM-1 in endothelial cells.The expression of ICAM-1 in the low-stress group was more significant than that in the static group.9.Higher UA(9mg/dl)increased the adhesion of THP-1 cells to endothelial cells,lower shear stress induced more moncytes to endothelial cells.Conclusions:1.SUA is an independent risk factor for SAAS in asymptomatic middle-aged Chinese population,with the vertebral arteries being the most frequently affected extracranial supra-aortic vessels.2.We first found that higher uric acid level(9mg/dl)initiates(P)RR expression of HUVECs.Lower shear stress increases the expression of(P)RR.3.The expression of ICAM-1 in HUVECs increases with higher uric acid.Higher uric acid promotes adhesion between vascular endothelial cells and monocytes.4.In the simulated hemodynamic observation,lower shear stress makes more significant adhesion between monocytes and vascular endothelium,and may therefore mediate vascular endothelial injury,and develop to atherosclerosis.