Uric acid as a mediator of endothelial dysfunction, inflammation, and vascular disease

doi:10.1016/j.semnephrol.2004.09.007

Seminars in Nephrology

Volume 25, Issue 1, January 2005, Pages 39-42

https://doi.org/10.1016/j.semnephrol.2004.09.007 Get rights and content

Recent experimental findings have led to renewed interest in the possible role of uric acid in the pathogenesis of both hypertension and vascular disease. Often considered an antioxidant, biochemical and in vitro data indicate that noncrystalline, soluble uric acid also can react to form radicals, increase lipid oxidation, and induce various pro-oxidant effects in vascular cells. In vitro and in vivo findings suggest that uric acid may contribute to endothelial dysfunction by inducing antiproliferative effects on endothelium and impairing nitric oxide production. Proinflammatory and proliferative effects of soluble uric acid have been described on vascular smooth muscle cells (VSMCs), and in animal models of mild hyperuricemia, hypertension develops in association with intrarenal vascular disease. Possible adverse effects of uric acid on the vasculature have been linked to increased chemokine and cytokine expression, induction of the renin-angiotensin system, and to increased vascular C-reactive protein (CRP) expression. Experimental evidence suggests a complex but potentially direct causal role for uric acid in the pathogenesis of hypertension and atherosclerosis.

Section snippets

Whether uric acid is an anti- or pro-oxidant may depend on the cellular enviornment

Uric acid is a product of purine metabolism, formed from the breakdown of adenosine and guanine. It is produced from hypoxanthine and xanthine via the action of the enzyme xanthine oxidase; oxidants also are generated during this process. Local and circulating urate levels are influenced significantly by tissue oxygenation and hemodynamic factors among other things (eg, dietary, genetic, drug-related, and renal factors). When tissue becomes ischemic, adenosine triphosphate breakdown, xanthine

Hyperuricemia and endothelial dysfunction

Cardiovascular disease commonly is associated with endothelial dysfunction, oxidant generation, and a pro-inflammatory state.17 Oxidants generated via xanthine oxidase potentially can cause endothelial dysfunction through effects on nitric oxide synthesis and availability. Xanthine oxidase also produces uric acid, which may explain why hyperuricemia, oxidant generation, and endothelial dysfunction all are associated.

What is the exact role of uric acid in this setting? Is it protective, inert,

Proliferative and proinflammatory effects of uric acid on vascular smooth muscle

Soluble uric acid has been shown to induce vascular smooth muscle cell (VSMC) proliferation in vitro via a pathway involving increased platelet-derived growth factor-A expression.29 Our studies have confirmed this observation and also shown that uric acid-induced VSMC proliferation is mediated by the activation or induction of extracellular signal-regulated kinase mitogen-activated protein kinases (MAPK) and cyclooxygenase-2.30, 31

Adding further to this pathway, we recently showed that

Other pro-atherogenic pathways: a possible link with C-reactive protein

We also recently found that uric acid up-regulates C-reactive protein (CRP) expression in cultured human vascular cells, namely VSMCs and endothelial cells.40 Given the many recent insights regarding the role of CRP as an active partaker rather than just as a simple marker of vascular inflammation,41 uric acid-induced CRP expression by vascular cells may provide further direct evidence for both proinflammatory and proatherogenic effects of uric acid.

Lessons from animal models of hyperuricemia

Several more pieces of evidence suggesting that uric acid is a mediator of endothelial dysfunction, vascular disease, and inflammation have arisen from various animal experiments.19, 20, 30, 31, 42 Briefly, experimental animal models generated by feeding rats the uricase inhibitor oxonic acid, have mildly increased serum uric acid levels associated with intrarenal vascular disease and salt-sensitive hypertension.19, 20, 30, 31, 42 Activation of the renin-angiotensin system is evident as is mild

Conclusion

Many of the studies summarized here have reawakened an old debate regarding the precise significance of increased serum uric acid levels. Although biochemical, cellular, animal model, and epidemiologic evidence exists that appears strongly suggestive of a causal role for uric acid in hypertension and vascular disease, much controversy still remains. Deciphering the complex role uric acid potentially has in the pathogenesis of both vascular disease and hypertension will require further

References (42)

J.T. Moriarity et al.
Serum uric acid and risk of coronary heart diseaseAtherosclerosis Risk in Communities (ARIC) Study
Ann Epidemiol
(2000)
G.L. Squadrito et al.
Reaction of uric acid with peroxynitrite and implications for the mechanism of neuroprotection by uric acid
Arch Biochem Biophys
(2000)
K.R. Maples et al.
Free radical metabolite of uric acid
J Biol Chem
(1988)
C.X. Santos et al.
Uric acid oxidation by peroxynitriteMultiple reactions, free radical formation, and amplification of lipid oxidation
Arch Biochem Biophys
(1999)
P.M. Abuja
Ascorbate prevents prooxidant effects of urate in oxidation of human low density lipoprotein
FEBS Lett
(1999)
R.A. Patterson et al.
Prooxidant and antioxidant properties of human serum ultrafiltrates toward LDLImportant role of uric acid
J Lipid Res
(2003)
J.G. Coghlan et al.
Allopurinol pretreatment improves postoperative recovery and reduces lipid peroxidation in patients undergoing coronary artery bypass grafting
J Thorac Cardiovasc Surg
(1994)
W.D. Johnson et al.
A randomized controlled trial of allopurinol in coronary bypass surgery
Am Heart J
(1991)
G.N. Rao et al.
Uric acid stimulates vascular smooth muscle cell proliferation by increasing platelet-derived growth factor A-chain expression
J Biol Chem
(1991)
T.J. Reape et al.
Chemokines and atherosclerosis
Atherosclerosis
(1999)

H.S. Goldstein et al.

Relation between serum uric acid and blood pressure in adolescents

Ann Hum Biol

(1993)

J.V. Selby et al.

Precursors of essential hypertensionPulmonary function, heart rate, uric acid, serum cholesterol, and other serum chemistries

Am J Epidemiol

(1990)

J. Fang et al.

Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study, 1971–1992. National Health and Nutrition Examination Survey

JAMA

(2000)

S.D. Anker et al.

Uric acid and survival in chronic heart failureValidation and application in metabolic, functional, and hemodynamic staging

Circulation

(2003)

C.J. Weir et al.

Serum urate as an independent predictor of poor outcome and future vascular events after acute stroke

Stroke

(2003)

A. Chamorro et al.

Yin and yang of uric acid in patients with stroke

Stroke

(2004)

B.N. Ames et al.

Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancerA hypothesis

Proc Natl Acad Sci U S A

(1981)

M. Hicks et al.

Identification of products from oxidation of uric acid induced by hydroxyl radicals

Free Radic Res Commun

(1993)

M. Bagnati et al.

When and why a water-soluble antioxidant becomes pro-oxidant during copper-induced low-density lipoprotein oxidationA study using uric acid

Biochem J

(1999)

A. Cherubini et al.

Antioxidant profile and early outcome in stroke patients

Stroke

(2000)

F. Leyva et al.

Serum uric acid as an index of impaired oxidative metabolism in chronic heart failure

Eur Heart J

(1997)

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After adjusting for covariates, the cross-lagged path coefficients (β₁) from baseline SUA to follow-up SBP and DBP were significantly greatly than path coefficients (β₂) from baseline SBP and DBP to follow-up SUA (β₁=0.041 versus β₂=0.003; P_difference<0.0001 for SBP; β₁=0.040 versus β₂=0.000; P_difference<0.0001 for DBP). The path coefficients from baseline SUA to follow-up SBP and DBP in group with incident CVD were significantly greatly than that in group without incident CVD (P_difference of β₁ in the two groups was 0.0018 for SBP and 0.0340 for DBP). Furthermore, SBP and DBP partially mediated the effect of SUA on incident CVD, the mediation effect was 57.64% for SBP and 46.27% for DBP. Similar mediated results were observed for stroke and myocardial infarction.
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: Supported in part by National Institutes of Health grants DK-52121 and HL-68607; the George O’Brien Center (1P50-DK064233-01); National Health and Medical Research Council, Australia; Don and Lorraine Jacquot Fellowship and Jacquot Research Establishment Awards, Australia (J.K.); and grant R04-2002-000-00183-0 from the Basic Research Program of the Korea Science and Engineering Foundation (D.-H.K.).

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Uric acid as a mediator of endothelial dysfunction, inflammation, and vascular disease

Section snippets

Whether uric acid is an anti- or pro-oxidant may depend on the cellular enviornment

Hyperuricemia and endothelial dysfunction

Proliferative and proinflammatory effects of uric acid on vascular smooth muscle

Other pro-atherogenic pathways: a possible link with C-reactive protein

Lessons from animal models of hyperuricemia

Conclusion

Ann Epidemiol

Arch Biochem Biophys

J Biol Chem

Arch Biochem Biophys

FEBS Lett

J Lipid Res

J Thorac Cardiovasc Surg

Am Heart J

J Biol Chem

Atherosclerosis

Relation between serum uric acid and blood pressure in adolescents

Ann Hum Biol

Precursors of essential hypertensionPulmonary function, heart rate, uric acid, serum cholesterol, and other serum chemistries

Am J Epidemiol

Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study, 1971–1992. National Health and Nutrition Examination Survey

JAMA

Uric acid and survival in chronic heart failureValidation and application in metabolic, functional, and hemodynamic staging

Circulation

Serum urate as an independent predictor of poor outcome and future vascular events after acute stroke

Stroke

Yin and yang of uric acid in patients with stroke

Stroke

Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancerA hypothesis

Proc Natl Acad Sci U S A

Identification of products from oxidation of uric acid induced by hydroxyl radicals

Free Radic Res Commun

When and why a water-soluble antioxidant becomes pro-oxidant during copper-induced low-density lipoprotein oxidationA study using uric acid

Biochem J

Antioxidant profile and early outcome in stroke patients

Stroke

Serum uric acid as an index of impaired oxidative metabolism in chronic heart failure

Eur Heart J