The role of hyperuricemia on vascular endothelium dysfunction

Zhen,Haitao; Gui,Fen

doi:10.3892/br.2017.966

The role of hyperuricemia on vascular endothelium dysfunction

Authors:
- Haitao Zhen
- Fen Gui
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Affiliations: Department of Internal Medicine, School of Medicine, Hubei University of Science and Technology, Xianning, Hubei 437100, P.R. China, Xianning Central Hospital, Xianning, Hubei 437100, P.R. China
Published online on: August 9, 2017 https://doi.org/10.3892/br.2017.966
Pages: 325-330

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Abstract

Hyperuricemia appears to be associated with an increased risk for cardiovascular disease and associated mortality. Population epidemiological data support a causal link between hyperuricemia and cardiovascular disease. Endothelium injury could be one of the potential mechanisms in hyperuricemia‑induced cardiovascular disease. However, the specific role of uric acid (UA) in the impairment of vascular relaxation and its signal transduction pathway has not been examined. The authors investigated the role of UA on vascular relaxation, nitric oxide (NO) production and expression of proinflammatory cytokines. Brachial flow‑mediated dilation and nitroglycerine‑mediated dilation were measured by B‑mode ultrasound with 10 megahertz linear‑array transducer from 21 patients with hyperuricemia and 16 control subjects. Human umbilical vein endothelial cells (ECs) were incubated with UA (5‑15 mg/dl) with or without nuclear factor (NF)‑κB inhibitor II. Hyperuricemia inhibited brachial flow‑mediated dilation. While UA significantly inhibited NO expression with time course‑ and dose‑ dependent manner in the cultured ECs, 10 mg/dl UA also increased expression of inflammation cytokine interleukin (IL)‑6, IL‑8 and tumor necrosis factor‑α in vitro. These abnormalities were associated with UA‑induced activation of transcription factor NF‑κB. Furthermore, NF‑κB inhibitor II prevented UA-induced reduction of NO and increased inflammation cytokines. These data suggested hyperuricemia‑induced endothelium injury and vascular dysfunction by a reduction of NO and expression of inflammatory cytokines through the NF-κB pathway.

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1	Mallat SG, Al Kattar S, Tanios BY and Jurjus A: Hyperuricemia, Hypertension, and Chronic Kidney Disease: An Emerging Association. Curr Hypertens Rep. 18:742016. View Article : Google Scholar : PubMed/NCBI
2	Essex MN, Hopps M, Bienen EJ, Udall M, Mardekian J and Makinson GT: Evaluation of the relationship between serum uric acid levels and cardiovascular events in patients with gout: A retrospective analysis using electronic medical record data. J Clin Rheumatol. 23:160–166. 2017. View Article : Google Scholar : PubMed/NCBI
3	Bos MJ, Koudstaal PJ, Hofman A, Witteman JC and Breteler MM: Uric acid is a risk factor for myocardial infarction and stroke: The Rotterdam study. Stroke. 37:1503–1507. 2006. View Article : Google Scholar : PubMed/NCBI
4	Fang J and Alderman MH: Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study, 1971–1992. National Health and Nutrition Examination Survey. JAMA. 283:2404–2410. 2000. View Article : Google Scholar : PubMed/NCBI
5	Ford ES, Li C, Cook S and Choi HK: Serum concentrations of uric acid and the metabolic syndrome among US children and adolescents. Circulation. 115:2526–2532. 2007. View Article : Google Scholar : PubMed/NCBI
6	Lehto S, Niskanen L, Rönnemaa T and Laakso M: Serum uric acid is a strong predictor of stroke in patients with non-insulin-dependent diabetes mellitus. Stroke. 29:635–639. 1998. View Article : Google Scholar : PubMed/NCBI
7	Li P, Zhang L, Zhang M, Zhou C and Lin N: Uric acid enhances PKC-dependent eNOS phosphorylation and mediates cellular ER stress: A mechanism for uric acid-induced endothelial dysfunction. Int J Mol Med. 37:989–997. 2016.PubMed/NCBI
8	Cai W, Duan XM, Liu Y, Yu J, Tang YL, Liu ZL, Jiang S, Zhang CP, Liu JY and Xu JX: Uric Acid Induces Endothelial Dysfunction by Activating the HMGB1/RAGE Signaling Pathway. BioMed Res Int. 2017:43919202017. View Article : Google Scholar : PubMed/NCBI
9	Wong CK, Chen Y, Ho LM, Zhen Z, Siu CW, Tse HF and Yiu KH: The effects of hyperuricaemia on flow-mediated and nitroglycerin-mediated dilatation in high-risk patients. Nutr Metab Cardiovasc Dis. 24:1012–1019. 2014. View Article : Google Scholar : PubMed/NCBI
10	Naka KK, Papathanassiou K, Bechlioulis A, Kazakos N, Pappas K, Tigas S, Makriyiannis D, Tsatsoulis A and Michalis LK: Determinants of vascular function in patients with type 2 diabetes. Cardiovasc Diabetol. 11:1272012. View Article : Google Scholar : PubMed/NCBI
11	Calvert JW: Cardioprotective effects of nitrite during exercise. Cardiovasc Res. 89:499–506. 2011. View Article : Google Scholar : PubMed/NCBI
12	Wang R, Zhang Y, Xu L, Lin Y, Yang X, Bai L, Chen Y, Zhao S, Fan J, Cheng X, et al: Protein Inhibitor of Activated STAT3 Suppresses Oxidized LDL-induced Cell Responses during Atherosclerosis in Apolipoprotein E-deficient Mice. Sci Rep. 6:367902016. View Article : Google Scholar : PubMed/NCBI
13	Slanina H, Schmutzler M, Christodoulides M, Kim KS and Schubert-Unkmeir A: Effective plasmid DNA and small interfering RNA delivery to diseased human brain microvascular endothelial cells. J Mol Microbiol Biotechnol. 22:245–257. 2012. View Article : Google Scholar : PubMed/NCBI
14	Zhang D, Atlasi SS, Patel KK, Zhuang Z and Heaney AP: False responses of Renilla luciferase reporter control to nuclear receptor TR4. Mol Cell Biochem. 430:139–147. 2017. View Article : Google Scholar : PubMed/NCBI
15	Ding XH, Wang X, Cao R, Yang X, Xiao W, Zhang Y, Bai Y, Wu H and Ye P: A higher baseline plasma uric acid level is an independent predictor of arterial stiffness: A community-based prospective study. Medicine (Baltimore). 96:e59572017. View Article : Google Scholar : PubMed/NCBI
16	Volterrani M, Iellamo F, Sposato B and Romeo F: Uric acid lowering therapy in cardiovascular diseases. Int J Cardiol. 213:20–22. 2016. View Article : Google Scholar : PubMed/NCBI
17	Huang J, Sun Y, Niu K, Wan Z, Yao W, Gao Y, Zhang W, Li Y, Zhao H and Wu X: Does elevated serum uric acid level predict the hypertension incidence? A Chinese prospective cohort study. Clin Exp Hypertens. 37:498–504. 2015. View Article : Google Scholar : PubMed/NCBI
18	Yang TY, Fang CY, Chen JS, Po HL, Chou LP, Chiang CY and Ueng KC: Association of Serum Uric Acid with Cardiovascular Disease in Taiwanese Patients with Primary Hypertension. Acta Cardiol Sin. 31:42–51. 2015.PubMed/NCBI
19	McCarthy CG, Goulopoulou S, Wenceslau CF, Spitler K, Matsumoto T and Webb RC: Toll-like receptors and damage-associated molecular patterns: Novel links between inflammation and hypertension. Am J Physiol Heart Circ Physiol. 306:H184–H196. 2014. View Article : Google Scholar : PubMed/NCBI
20	Verdoia M, Barbieri L, Schaffer A, Cassetti E, Nardin M, Bellomo G, Aimaretti G, Marino P, Sinigaglia F and De Luca G: Novara Atherosclerosis Study Group (NAS): Impact of diabetes on uric acid and its relationship with the extent of coronary artery disease and platelet aggregation: A single-centre cohort study. Metabolism. 63:640–646. 2014. View Article : Google Scholar : PubMed/NCBI
21	Borghi C and Desideri G: Urate-lowering drugs and prevention of cardiovascular disease: The emerging role of xanthine oxidase inhibition. Hypertension. 67:496–498. 2016.PubMed/NCBI
22	Kaneko C, Ogura J, Sasaki S, Okamoto K, Kobayashi M, Kuwayama K, Narumi K and Iseki K: Fructose suppresses uric acid excretion to the intestinal lumen as a result of the induction of oxidative stress by NADPH oxidase activation. Biochim Biophys Acta. 1861:559–566. 2017. View Article : Google Scholar : PubMed/NCBI
23	Spiga R, Marini MA, Mancuso E, Di Fatta C, Fuoco A, Perticone F, Andreozzi F, Mannino GC and Sesti G: Uric acid is associated with inflammatory biomarkers and induces inflammation via activating the NF-κB Signaling Pathway in HepG2 Cells. Arterioscler Thromb Vasc Biol. 37:1241–1249. 2017. View Article : Google Scholar : PubMed/NCBI
24	Luo C, Lian X, Hong L, Zou J, Li Z, Zhu Y, Huang T, Zhang Y, Hu Y, Yuan H, et al: High Uric Acid Activates the ROS-AMPK Pathway, Impairs CD68 Expression and Inhibits OxLDL-Induced Foam-Cell Formation in a Human Monocytic Cell Line, THP-1. Cell Physiol Biochem. 40:538–548. 2016. View Article : Google Scholar : PubMed/NCBI
25	Lee KS, Kim J, Kwak SN, Lee KS, Lee DK, Ha KS, Won MH, Jeoung D, Lee H, Kwon YG, et al: Functional role of NF-κB in expression of human endothelial nitric oxide synthase. Biochem Biophys Res Commun. 448:101–107. 2014. View Article : Google Scholar : PubMed/NCBI
26	Grumbach IM, Chen W, Mertens SA and Harrison DG: A negative feedback mechanism involving nitric oxide and nuclear factor kappa-B modulates endothelial nitric oxide synthase transcription. J Mol Cell Cardiol. 39:595–603. 2005. View Article : Google Scholar : PubMed/NCBI