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Hyperuricemia and endothelial function: From molecular background to clinical perspectives

  • Tatsuya Maruhashi
    Affiliations
    Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan
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  • Ichiro Hisatome
    Affiliations
    Division of Regenerative Medicine and Therapeutics, Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University Graduate School of Medical Science, Yonago, Japan
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  • Yasuki Kihara
    Affiliations
    Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan
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  • Yukihito Higashi
    Correspondence
    Corresponding author. Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine (RIRBM), Hiroshima University 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
    Affiliations
    Division of Regeneration and Medicine, Hiroshima University Hospital, Hiroshima, Japan

    Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
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Open AccessPublished:October 06, 2018DOI:https://doi.org/10.1016/j.atherosclerosis.2018.10.007

      Highlights

      • Uric acid is the end product of purine metabolism catalyzed by xanthine oxidase.
      • Reactive oxygen species are concomitantly generated with uric acid production.
      • Xanthine oxidase may be a therapeutic target of endothelial dysfunction.
      • Experimental studies have shown that uric acid per se causes endothelial dysfunction.
      • Biological effect of uric acid on endothelial function in vivo and in a clinical setting is not established.

      Abstract

      Uric acid is the end product of purine metabolism catalyzed by xanthine oxidase in humans. In the process of purine metabolism, reactive oxygen species, including superoxide, are generated concomitantly with uric acid production, which may deteriorate endothelial function through the reaction of superoxide with nitric oxide (NO), leading to decreased NO bioavailability and increased production of peroxynitrite, a reactive oxidant. Therefore, xanthine oxidase may be a therapeutic target in the treatment of endothelial dysfunction. Indeed, clinical studies have shown that endothelial dysfunction is restored by treatment with a xanthine oxidase inhibitor in patients with cardiovascular risk factors. However, it has not been fully determined whether uric acid per se is an independent causal risk factor of endothelial dysfunction in humans. Although experimental studies have indicated that uric acid absorbed into endothelial cells via the activation of uric acid transporters expressed in endothelial cells causes endothelial dysfunction through increased oxidative stress and inflammation, an actual biological effect of uric acid on endothelial function in vivo has not been fully elucidated, in part, because of the difficulty in investigating the effect of uric acid alone on endothelial function due to the close associations of uric acid with other conventional cardiovascular risk factors and the complicated relationship between uric acid and endothelial function attributed to the potent antioxidant properties of uric acid. In this review, we focus on the relationship between uric acid and endothelial function from molecular to clinical perspectives.

      Keywords

      1. Introduction

      Serum uric acid level is closely associated with established cardiovascular risk factors such as hypertension [
      • Cannon P.J.
      • Stason W.B.
      • Demartini F.E.
      • et al.
      Hyperuricemia in primary and renal hypertension.
      ], chronic kidney disease [
      • Siu Y.P.
      • Leung K.T.
      • Tong M.K.
      • et al.
      Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level.
      ], and metabolic syndrome [
      • Ford E.S.
      • Li C.
      • Cook S.
      • et al.
      Serum concentrations of uric acid and the metabolic syndrome among US children and adolescents.
      ]. Serum uric acid levels are higher in patients with these risk factors than in individuals without the risk factors. Recent epidemiological studies have also shown that the serum uric acid level is associated with the development of hypertension, dyslipidemia, diabetes mellitus, chronic kidney disease, and atrial fibrillation [
      • Kuwabara M.
      • Niwa K.
      • Nishihara S.
      • et al.
      Hyperuricemia is an independent competing risk factor for atrial fibrillation.
      ,
      • Kuwabara M.
      • Niwa K.
      • Hisatome I.
      • et al.
      Asymptomatic hyperuricemia without comorbidities predicts cardiometabolic diseases: five-year Japanese cohort study.
      ,
      • Kuwabara M.
      • Kuwabara R.
      • Hisatome I.
      • et al.
      "Metabolically healthy" obesity and hyperuricemia increase risk for hypertension and diabetes: 5-year Japanese cohort study.
      ,
      • Kuwabara M.
      • Hisatome I.
      • Niwa K.
      • et al.
      Uric acid is a strong risk marker for developing hypertension from prehypertension: a 5-year Japanese cohort study.
      ,
      • Kuwabara M.
      • Borghi C.
      • Cicero A.F.G.
      • et al.
      Elevated serum uric acid increases risks for developing high LDL cholesterol and hypertriglyceridemia: a five-year cohort study in Japan.
      ] as well as the occurrence of cardiovascular events [
      • Reunanen A.
      • Takkunen H.
      • Knekt P.
      • et al.
      Hyperuricemia as a risk factor for cardiovascular mortality.
      ,
      • Alderman M.H.
      • Cohen H.
      • Madhavan S.
      • et al.
      Serum uric acid and cardiovascular events in successfully treated hypertensive patients.
      ,
      • Culleton B.F.
      • Larson M.G.
      • Kannel W.B.
      • et al.
      Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study.
      ,
      • Fang J.
      • Alderman M.H.
      Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study, 1971-1992. National Health and Nutrition Examination Survey.
      ]. Therefore, an increase in serum uric acid level is considered to be a marker of increased cardiovascular risk. Endothelial dysfunction is involved in the development and progression of atherosclerosis, leading to cardiovascular complications [
      • Ross R.
      Atherosclerosis--an inflammatory disease.
      ,
      • Higashi Y.
      • Noma K.
      • Yoshizumi M.
      • et al.
      Endothelial function and oxidative stress in cardiovascular diseases.
      ]. It is well known that traditional coronary risk factors, including hypertension, dyslipidemia, diabetes mellitus, smoking habit, obesity, and menopause, are associated with endothelial dysfunction. Experimental studies have demonstrated that hyperuricemia provokes endothelial dysfunction through increases in inflammation and oxidative stress. Recent clinical studies have also shown that hyperuricemia is associated with endothelial dysfunction in humans. Experimental and clinical studies have suggested that uric acid is not only a biomarker of cardiovascular risk but also a causal risk factor of endothelial dysfunction. However, it has not been fully determined whether uric acid per se is an independent causal risk factor of endothelial dysfunction, in part, because of the difficulty in investigating the role of uric acid alone in the pathogenesis of endothelial dysfunction due to the strong associations of uric acid with other risk factors such as hypertension, metabolic syndrome, chronic kidney disease, menopausal status, alcohol intake, and use of diuretics. In addition, uric acid is a potent antioxidant, making the relationship between uric acid and endothelial dysfunction more complicated. This review focuses on the underlying mechanisms of endothelial dysfunction associated with hyperuricemia and clinical data about the relationship between endothelial function and uric acid.

      1.1 Endothelial function

      The endothelium functions not only as a structural barrier separating the inside cavity and the blood vessel wall but also an endocrine organ secreting a wide range of vasoactive agents, including vasodilators such as nitric oxide (NO), prostaglandin I2, and endothelium-derived hyperpolarizing factor and the vasoconstrictors such as endothelin-1, thromboxane A2, and angiotensin II [
      • Vane J.R.
      • Anggard E.E.
      • Botting R.M.
      Regulatory functions of the vascular endothelium.
      ], among which NO plays a critical role in the prevention of atherosclerosis. A healthy endothelium plays a key role not only in the control of vascular tone but also in maintenance of vascular homeostasis by regulating the balances between vasoconstriction and vasodilation, growth promotion and growth inhibition, pro-thrombosis and anti-thrombosis, pro-inflammation and anti-inflammation, and pro-oxidation and anti-oxidation. Endothelial dysfunction refers to a condition in which vascular homeostasis is disturbed as a result of an imbalance between endothelium-derived vasodilating factors and vasoconstricting factors, leading to the progression of atherosclerosis. Considering the various anti-atherosclerotic effects of NO, such as vasodilation, suppression of vascular smooth muscle cell proliferation, inhibition of leukocyte adhesion, and inhibition of platelet aggregation and adhesion, reduced NO bioavailability (decreased NO production and/or increased NO inactivation) is generally referred to as endothelial dysfunction [
      • Cai H.
      • Harrison D.G.
      Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress.
      ]. Although endothelial function is impaired in patients with hyperuricemia, it has not been fully determined whether hyperuricemia itself is a causal risk factor for endothelial dysfunction. Recent experimental and clinical studies have indicated the possibility that hyperuricemia is causally related to endothelial dysfunction.

      1.2 Proposed mechanisms underlying endothelial dysfunction associated with hyperuricemia

      1.2.1 Xanthine oxidase and endothelial NO synthase (eNOS) uncoupling

      Xanthine oxidoreductase is a molybdoenzyme catalyzing the oxidation of hypoxanthine to xanthine and xanthine to urate in the process of purine metabolism [
      • Berry C.E.
      • Hare J.M.
      Xanthine oxidoreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications.
      ]. Xanthine oxidoreductase exists in two interconvertible but functionally distinct forms: xanthine dehydrogenase (XD) and xanthine oxidase (XO). XD is the constitutively expressed form in vivo, whereas XO is the post-transcriptionally modified form that is highly expressed under certain physiological and pathophysiological conditions, such as hypoxia and ischemia [
      • Zweier J.L.
      • Kuppusamy P.
      • Lutty G.A.
      Measurement of endothelial cell free radical generation: evidence for a central mechanism of free radical injury in postischemic tissues.
      ,
      • Doehner W.
      • Anker S.D.
      Uric acid in chronic heart failure.
      ]. XD preferentially uses NAD+ as an electron acceptor to catalyze the conversion of hypoxanthine to xanthine and xanthine to urate, resulting in the generation of the stable reaction product NADH, whereas XO preferentially uses molecular oxygen as an electron acceptor for the purine oxidation, leading to the generation of superoxide anion (O2) and hydrogen peroxide (H2O2) [
      • Saito T.
      • Nishino T.
      Differences in redox and kinetic properties between NAD-dependent and O2-dependent types of rat liver xanthine dehydrogenase.
      ,
      • Meneshian A.
      • Bulkley G.B.
      The physiology of endothelial xanthine oxidase: from urate catabolism to reperfusion injury to inflammatory signal transduction.
      ]. Therefore, under a condition in which the activity of XO is enhanced for catalyzing the process of purine metabolism, not only uric acid but also reactive oxygen species (ROS) are generated concomitantly, which could have a deleterious effect on endothelial function (Fig. 1). Excessively generated O2 concomitant with increased uric acid production in the process of purine metabolism reacts directly with NO with high affinity, resulting not only in decreased NO bioavailability through degradation and inactivation of NO but also in increased formation of peroxynitrite (ONOO), a highly potent oxidant causing DNA damage, cell death, and lipid peroxidation. ONOO can oxidize tetrahydrobiopterin, the essential eNOS cofactor, to the biologically inactive trihydrobiopterin, leading to a deficiency of tetrahydrobiopterin. In the absence of adequate concentrations of tetrahydrobiopterin, eNOS is converted from an NO-producing enzyme into an O2-generating enzyme. This process is referred to as eNOS uncoupling [
      • Forstermann U.
      • Sessa W.C.
      Nitric oxide synthases: regulation and function.
      ]. Under the condition in which production of O2 is once increased, endothelial function is further impaired through a vicious cycle of increased oxidative stress, decreased NO bioavailability, increased ONOO production, and eNOS uncoupling, with a further increase in O2 production and a further decrease in NO bioavailability. Therefore, it is postulated that bioavailability of NO is decreased by generated O2 concomitant with uric acid production in the process of purine metabolism catalyzed by XO, leading to endothelial dysfunction.
      Fig. 1
      Fig. 1Putative mechanisms underlying endothelial dysfunction induced by hyperuricemia.
      NO, nitric oxide; ONOO, peroxynitrite; eNOS, endothelial NO synthase; URATv1, voltage-driven urate transporter 1; EC, endothelial cell.
      XO exists not only within the cytoplasm of endothelial cells but also on the outside surface of the endothelial cell membrane. Experimental studies have revealed the possibility that circulating XO released from XO-rich organs under pathophysiological conditions is bound to glycosaminoglycans on the surface of endothelial cells and may be subsequently endocytosed into intracellular compartments, resulting in the inhibition of NO-dependent vascular smooth muscle cell relaxation [
      • Houston M.
      • Estevez A.
      • Chumley P.
      • et al.
      Binding of xanthine oxidase to vascular endothelium. Kinetic characterization and oxidative impairment of nitric oxide-dependent signaling.
      ]. These findings suggest that not only XO produced endogenously in endothelial cells but also inducible circulating XO released from XO-rich organs is an important source of ROS contributing to endothelial dysfunction [
      • Panus P.C.
      • Wright S.A.
      • Chumley P.H.
      • et al.
      The contribution of vascular endothelial xanthine dehydrogenase/oxidase to oxygen-mediated cell injury.
      ].
      Xanthine oxidoreductase has been shown to be involved in the transformation of macrophages into foam cells [
      • Kushiyama A.
      • Okubo H.
      • Sakoda H.
      • et al.
      Xanthine oxidoreductase is involved in macrophage foam cell formation and atherosclerosis development.
      ]. The retention and accumulation of cholesterol-rich apolipoprotein-B-containing lipoproteins within the arterial intima is thought to be the key initial event in the pathogenesis of atherosclerosis, leading to a series of maladaptive local responses that cause plaque development [
      • Ference B.A.
      • Ginsberg H.N.
      • Graham I.
      • et al.
      Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel.
      ,
      • Camejo G.
      • Hurt-Camejo E.
      • Wiklund O.
      • et al.
      Association of apo B lipoproteins with arterial proteoglycans: pathological significance and molecular basis.
      ,
      • Boren J.
      • Williams K.J.
      The central role of arterial retention of cholesterol-rich apolipoprotein-B-containing lipoproteins in the pathogenesis of atherosclerosis: a triumph of simplicity.
      ]. In the process of atherosclerosis, retained low-density lipoprotein (LDL) is taken up by macrophages that migrate into pathological lesions, resulting in the development of macrophages into foam cells. A recent study has shown that uptake of LDL into macrophages is accelerated by the activation of xanthine oxidoreductase, indicating that xanthine oxidoreductase is directly involved in the progression of atherosclerosis [
      • Kushiyama A.
      • Okubo H.
      • Sakoda H.
      • et al.
      Xanthine oxidoreductase is involved in macrophage foam cell formation and atherosclerosis development.
      ].

      1.2.2 Uric acid transporter

      Experimental studies have indicated the possibility that uric acid absorbed into endothelial cells via activation of uric acid transporters expressed in endothelial cells causes endothelial dysfunction (Fig. 1). In humans, about 90% of uric acid filtered at the glomeruli is reabsorbed by the renal tubules. Uric acid is reabsorbed into proximal tubular cells via the urate transporter 1 (URAT1) localized on the luminal (apical) side of renal proximal tubules [
      • Enomoto A.
      • Kimura H.
      • Chairoungdua A.
      • et al.
      Molecular identification of a renal urate anion exchanger that regulates blood urate levels.
      ], and it exits the cells via voltage-driven urate transporter 1 (URATv1) located at the basolateral membrane [
      • Anzai N.
      • Ichida K.
      • Jutabha P.
      • et al.
      Plasma urate level is directly regulated by a voltage-driven urate efflux transporter URATv1 (SLC2A9) in humans.
      ]. URAT1 and URATv1 are regarded as physiologically important uric acid transporters, which act in tandem for urate reabsorption in renal tubules. Recent experimental studies have revealed that uric acid transporters are expressed not only in renal tubular cells but also in other types of cells including vascular endothelial cells [
      • Price K.L.
      • Sautin Y.Y.
      • Long D.A.
      • et al.
      Human vascular smooth muscle cells express a urate transporter.
      ,
      • Zhang Y.
      • Yamamoto T.
      • Hisatome I.
      • et al.
      Uric acid induces oxidative stress and growth inhibition by activating adenosine monophosphate-activated protein kinase and extracellular signal-regulated kinase signal pathways in pancreatic beta cells.
      ,
      • Sugihara S.
      • Hisatome I.
      • Kuwabara M.
      • et al.
      Depletion of uric acid due to SLC22A12 (URAT1) loss-of-function mutation causes endothelial dysfunction in hypouricemia.
      ,
      • Kang D.H.
      • Han L.
      • Ouyang X.
      • et al.
      Uric acid causes vascular smooth muscle cell proliferation by entering cells via a functional urate transporter.
      ]. Uric acid absorbed into endothelial cells via the uric acid transporters causes inflammation or oxidative stress, which contributes to endothelial dysfunction through a reduction of endothelial NO bioavailability. Experimental studies have indicated the possibility that uric acid-induced ROS generation is due to the activation of NADPH oxidase [
      • Sautin Y.Y.
      • Nakagawa T.
      • Zharikov S.
      • et al.
      Adverse effects of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress.
      ,
      • Verzola D.
      • Ratto E.
      • Villaggio B.
      • et al.
      Uric acid promotes apoptosis in human proximal tubule cells by oxidative stress and the activation of NADPH oxidase NOX 4.
      ,
      • Sanchez-Lozada L.G.
      • Soto V.
      • Tapia E.
      • et al.
      Role of oxidative stress in the renal abnormalities induced by experimental hyperuricemia, American journal of physiology.
      ]. Kang et al. demonstrated that uric acid reduced NO release in human umbilical vein endothelial cells (HUVEC) with an increase in C-reactive protein production through the activation of p38 and extracellular signal-regulated kinase 44/42 mitogen-activated protein kinases pathways and inhibited migration and proliferation of HUVEC. It was also shown that these uric acid-induced alterations were reversed by treatment with probenecid, a uric acid transporter inhibitor, in an in vitro study [
      • Kang D.H.
      • Han L.
      • Ouyang X.
      • et al.
      Uric acid causes vascular smooth muscle cell proliferation by entering cells via a functional urate transporter.
      ]. Yui et al. demonstrated that production of ROS and apoptosis and senescence of HUVEC were enhanced by uric acid through activation of the local renin-angiotensin system, particularly angiotensin II, in HUVEC and that probenecid suppressed uric acid-induced oxidative stress and inhibited senescence and apoptosis of HUVEC [
      • Yu M.A.
      • Sanchez-Lozada L.G.
      • Johnson R.J.
      • et al.
      Oxidative stress with an activation of the renin-angiotensin system in human vascular endothelial cells as a novel mechanism of uric acid-induced endothelial dysfunction.
      ]. Mishima et al. demonstrated that uric acid reduced NO production through eNOS dephosphorylation by activating uric acid transporters in HUVEC and that impairment of eNOS phosphorylation and reduced NO production were restored by urate transporter inhibitors such as benzbromarone, losartan, and irbesartan [
      • Mishima M.
      • Hamada T.
      • Maharani N.
      • et al.
      Effects of uric acid on the NO production of HUVECs and its restoration by urate lowering agents.
      ]. These findings suggest that uric acid absorbed into endothelial cells through uric acid transporters causes inflammation, oxidative stress, and dephosphorylation of eNOS, leading to endothelial dysfunction through decreased NO bioavailability. Although it had been postulated that uric acid was absorbed into endothelial cells through URAT1, recent experimental studies have indicated the possibility that URATv1 but not URAT1 plays an important role in the absorption of uric acid into endothelial cells since mRNA of URATv1 is detected in HUVEC, but that of URAT1 is not [
      • Sugihara S.
      • Hisatome I.
      • Kuwabara M.
      • et al.
      Depletion of uric acid due to SLC22A12 (URAT1) loss-of-function mutation causes endothelial dysfunction in hypouricemia.
      ,
      • Mishima M.
      • Hamada T.
      • Maharani N.
      • et al.
      Effects of uric acid on the NO production of HUVECs and its restoration by urate lowering agents.
      ]. Benzbromarone, probenecid, losartan, and irbesartan have been shown to have inhibitory effects on URATv1, as well as on URAT1 [
      • Enomoto A.
      • Kimura H.
      • Chairoungdua A.
      • et al.
      Molecular identification of a renal urate anion exchanger that regulates blood urate levels.
      ,
      • Anzai N.
      • Ichida K.
      • Jutabha P.
      • et al.
      Plasma urate level is directly regulated by a voltage-driven urate efflux transporter URATv1 (SLC2A9) in humans.
      ,
      • Mishima M.
      • Hamada T.
      • Maharani N.
      • et al.
      Effects of uric acid on the NO production of HUVECs and its restoration by urate lowering agents.
      ,
      • Nakamura M.
      • Anzai N.
      • Jutabha P.
      • et al.
      Concentration-dependent inhibitory effect of irbesartan on renal uric acid transporters.
      ]. Taken together, these findings suggest that uric acid absorbed into endothelial cells via URATv1 causes endothelial dysfunction by reducing NO bioavailability through increased inflammation and oxidative stress and decreased eNOS phosphorylation.

      1.3 Association of uric acid with endothelial function in clinical settings

      Although it is difficult to investigate the effect of uric acid alone on endothelial function due to the close associations of uric acid with other cardiovascular risk factors, recent clinical studies have indicated the possibility that uric acid is independently associated with endothelial dysfunction. Flow-mediated vasodilation (FMD), an index of endothelial function in humans, has been shown to be more impaired in patients with hyperuricemia than in those without hyperuricemia [
      • Mercuro G.
      • Vitale C.
      • Cerquetani E.
      • et al.
      Effect of hyperuricemia upon endothelial function in patients at increased cardiovascular risk.
      ,
      • Kato M.
      • Hisatome I.
      • Tomikura Y.
      • et al.
      Status of endothelial dependent vasodilation in patients with hyperuricemia.
      ,
      • Ho W.J.
      • Tsai W.P.
      • Yu K.H.
      • et al.
      Association between endothelial dysfunction and hyperuricaemia.
      ,
      • Tomiyama H.
      • Higashi Y.
      • Takase B.
      • et al.
      Relationships among hyperuricemia, metabolic syndrome, and endothelial function.
      ]. In addition, serum uric acid levels have been shown to correlate negatively with endothelial function in the conduit artery and microvasculature in male individuals with cardiovascular risk factors [
      • Maxwell A.J.
      • Bruinsma K.A.
      Uric acid is closely linked to vascular nitric oxide activity. Evidence for mechanism of association with cardiovascular disease.
      ], postmenopausal women [
      • Maruhashi T.
      • Nakashima A.
      • Soga J.
      • et al.
      Hyperuricemia is independently associated with endothelial dysfunction in postmenopausal women but not in premenopausal women.
      ,
      • Prasad M.
      • Matteson E.L.
      • Herrmann J.
      • et al.
      Uric acid is associated with inflammation, coronary microvascular dysfunction, and adverse outcomes in postmenopausal women.
      ], patients with non-diabetic chronic kidney disease [
      • Kanbay M.
      • Yilmaz M.I.
      • Sonmez A.
      • et al.
      Serum uric acid level and endothelial dysfunction in patients with nondiabetic chronic kidney disease.
      ], patients with never-treated hypertension [
      • Zoccali C.
      • Maio R.
      • Mallamaci F.
      • et al.
      Uric acid and endothelial dysfunction in essential hypertension.
      ], patients with masked hypertension [
      • Sincer I.
      • Kurtoglu E.
      • Caliskan M.
      • et al.
      Significant correlation between uric acid levels and flow-mediated dilatation in patients with masked hypertension.
      ], and patients on peritoneal dialysis [
      • Tang Z.
      • Cheng L.T.
      • Li H.Y.
      • et al.
      Serum uric acid and endothelial dysfunction in continuous ambulatory peritoneal dialysis patients.
      ], with an independent association between uric acid and endothelial function after adjustment for other risk factors. These findings suggest that serum uric acid level is an independent biomarker of endothelial function in humans, providing useful information for risk stratification in patients with cardiovascular risk factors. However, it remains controversial whether uric acid per se is causally associated with endothelial dysfunction in humans because of the cross-sectional design of those studies, which does not allow for establishment of a definitive causal relationship between uric acid and endothelial dysfunction.

      1.4 Treatment of endothelial dysfunction associated with hyperuricemia

      Considering the putative mechanisms underlying endothelial dysfunction associated with hyperuricemia, XO inhibitors and uricosuric agents having inhibitory effects on urate transporters are expected to improve endothelial dysfunction. Indeed, treatment with an XO inhibitor has been shown to improve endothelial function in clinical settings. Oral treatment with allopurinol, an XO inhibitor, for 1 week to 4 weeks has been shown to improve endothelial function in the microvasculature assessed by forearm venous occlusion plethysmography in type 2 diabetics with mild hypertension [
      • Butler R.
      • Morris A.D.
      • Belch J.J.
      • et al.
      Allopurinol normalizes endothelial dysfunction in type 2 diabetics with mild hypertension.
      ], heavy smokers [
      • Guthikonda S.
      • Sinkey C.
      • Barenz T.
      • et al.
      Xanthine oxidase inhibition reverses endothelial dysfunction in heavy smokers.
      ], and patients with chronic heart failure [
      • Doehner W.
      • Schoene N.
      • Rauchhaus M.
      • et al.
      Effects of xanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure: results from 2 placebo-controlled studies.
      ,
      • George J.
      • Carr E.
      • Davies J.
      • et al.
      High-dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid.
      ]. In addition, endothelial function in the microvasculature has been shown to be improved by co-infusion of an XO inhibitor, allopurinol or oxypurinol, or a single oral administration of allopurinol of 600 mg before the endothelial function test [
      • Guthikonda S.
      • Sinkey C.
      • Barenz T.
      • et al.
      Xanthine oxidase inhibition reverses endothelial dysfunction in heavy smokers.
      ,
      • Doehner W.
      • Schoene N.
      • Rauchhaus M.
      • et al.
      Effects of xanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure: results from 2 placebo-controlled studies.
      ,
      • Cardillo C.
      • Kilcoyne C.M.
      • Cannon 3rd, R.O.
      • et al.
      Xanthine oxidase inhibition with oxypurinol improves endothelial vasodilator function in hypercholesterolemic but not in hypertensive patients.
      ]. These findings suggest that endothelial function in the microvasculature is improved by both acute treatment and chronic treatment with an XO inhibitor. Endothelial function in the conduit artery assessed by FMD has also been shown to be improved by treatment with allopurinol in patients with sleep apnea [
      • El Solh A.A.
      • Saliba R.
      • Bosinski T.
      • et al.
      Allopurinol improves endothelial function in sleep apnoea: a randomised controlled study.
      ], metabolic syndrome [
      • Yiginer O.
      • Ozcelik F.
      • Inanc T.
      • et al.
      Allopurinol improves endothelial function and reduces oxidant-inflammatory enzyme of myeloperoxidase in metabolic syndrome.
      ], diabetes mellitus [
      • Dogan A.
      • Yarlioglues M.
      • Kaya M.G.
      • et al.
      Effect of long-term and high-dose allopurinol therapy on endothelial function in normotensive diabetic patients.
      ], chronic kidney disease [
      • Kao M.P.
      • Ang D.S.
      • Gandy S.J.
      • et al.
      Allopurinol benefits left ventricular mass and endothelial dysfunction in chronic kidney disease.
      ], and coronary artery disease [
      • Rajendra N.S.
      • Ireland S.
      • George J.
      • et al.
      Mechanistic insights into the therapeutic use of high-dose allopurinol in angina pectoris.
      ,
      • Rekhraj S.
      • Gandy S.J.
      • Szwejkowski B.R.
      • et al.
      High-dose allopurinol reduces left ventricular mass in patients with ischemic heart disease.
      ], although some studies have shown neutral effects of allopurinol on endothelial function [
      • Jalal D.I.
      • Decker E.
      • Perrenoud L.
      • et al.
      Vascular function and uric acid-lowering in stage 3 CKD.
      ,
      • Szwejkowski B.R.
      • Gandy S.J.
      • Rekhraj S.
      • et al.
      Allopurinol reduces left ventricular mass in patients with type 2 diabetes and left ventricular hypertrophy.
      ,
      • Borgi L.
      • McMullan C.
      • Wohlhueter A.
      • et al.
      Effect of uric acid-lowering agents on endothelial function: a randomized, double-blind, placebo-controlled trial.
      ,
      • Tousoulis D.
      • Andreou I.
      • Tsiatas M.
      • et al.
      Effects of rosuvastatin and allopurinol on circulating endothelial progenitor cells in patients with congestive heart failure: the impact of inflammatory process and oxidative stress.
      ,
      • Robertson A.J.
      • Struthers A.D.
      A randomized controlled trial of allopurinol in patients with peripheral arterial disease.
      ]. Recent meta-analyses have revealed that allopurinol therapy significantly improves FMD [
      • Xin W.
      • Mi S.
      • Lin Z.
      Allopurinol therapy improves vascular endothelial function in subjects at risk for cardiovascular diseases: a meta-analysis of randomized controlled trials.
      ,
      • Cicero A.F.G.
      • Pirro M.
      • Watts G.F.
      • et al.
      Effects of allopurinol on endothelial function: a systematic review and meta-analysis of randomized placebo-controlled trials.
      ]. In addition, a recent study showed that febuxostat, a novel nonpurine selective XO inhibitor, also improved FMD in hemodialysis patients with hyperuricemia [
      • Tsuruta Y.
      • Kikuchi K.
      • Tsuruta Y.
      • et al.
      Febuxostat improves endothelial function in hemodialysis patients with hyperuricemia: a randomized controlled study, Hemodialysis international.
      ]. These findings suggest that XO inhibitors improve endothelial function in patients with cardiovascular risk factors. However, since inhibition of XO may repress the generation of ROS and the production of uric acid simultaneously, it is difficult to determine whether improvement of endothelial function by treatment with XO inhibitors is due to the decrease in ROS generation or uric acid production. A recent meta-analysis showed that there was no significant association between increases in FMD and decreases in serum uric acid levels after allopurinol treatment, suggesting that improvement of FMD by the treatment with allopurinol is independent of the uric acid-lowering effect [
      • Cicero A.F.G.
      • Pirro M.
      • Watts G.F.
      • et al.
      Effects of allopurinol on endothelial function: a systematic review and meta-analysis of randomized placebo-controlled trials.
      ]. In addition, to our knowledge, there has been no study showing that treatment with urate transporter inhibitors improves endothelial function in humans [
      • George J.
      • Carr E.
      • Davies J.
      • et al.
      High-dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid.
      ,
      • Jalal D.I.
      • Decker E.
      • Perrenoud L.
      • et al.
      Vascular function and uric acid-lowering in stage 3 CKD.
      ]. Further studies are needed to determine whether uric acid per se is causally associated with endothelial function in humans.

      1.5 Uric acid as an antioxidant

      Uric acid is also known as a powerful antioxidant, which makes the relationship between uric acid and endothelial function more complicated. Febuxostat has been reported to decrease not only derivatives of reactive oxygen metabolites, an index of ROS, but also biological antioxidant potential, an indicator of antioxidant capacity, concomitant with a decrease in serum uric acid levels in hyperuricemic patients, raising the possibility that uric acid also serves as an antioxidant in humans [
      • Fukui T.
      • Maruyama M.
      • Yamauchi K.
      • et al.
      Effects of febuxostat on oxidative stress.
      ]. It was shown that the antioxidant effect of urate is comparable to that of ascorbate, an important antioxidant in plasma, in an in vitro study [
      • Ames B.N.
      • Cathcart R.
      • Schwiers E.
      • et al.
      Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis.
      ]. Plasma urate levels in humans are considerably higher than ascorbate levels. Therefore, urate is thought to be responsible for neutralizing more than 50% of the free radicals in human blood [
      • Glantzounis G.K.
      • Tsimoyiannis E.C.
      • Kappas A.M.
      • et al.
      Uric acid and oxidative stress.
      ]. In addition, an experimental study showed that physiological levels of uric acid prevented H2O2-induced inactivation of superoxide dismutase (SOD), an antioxidant enzyme capable of removing superoxide anion radicals, resulting in maintenance of SOD activity [
      • Hink H.U.
      • Santanam N.
      • Dikalov S.
      • et al.
      Peroxidase properties of extracellular superoxide dismutase: role of uric acid in modulating in vivo activity.
      ]. Moreover, urate has been shown to inhibits Fe3+-dependent ascorbate oxidation by forming complexes with Fe3+ as an iron chelator [
      • Davies K.J.
      • Sevanian A.
      • Muakkassah-Kelly S.F.
      • et al.
      Uric acid-iron ion complexes. A new aspect of the antioxidant functions of uric acid.
      ]. These experimental findings indicate that uric acid may function as an antioxidant through scavenging radical species, maintaining SOD activity, and chelating transition metals.
      Several epidemiological studies have shown J-shaped associations between serum uric acid levels and cardiovascular event risks [
      • Culleton B.F.
      • Larson M.G.
      • Kannel W.B.
      • et al.
      Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study.
      ,
      • Verdecchia P.
      • Schillaci G.
      • Reboldi G.
      • et al.
      Relation between serum uric acid and risk of cardiovascular disease in essential hypertension.
      ,
      • Kamei K.
      • Konta T.
      • Hirayama A.
      • et al.
      Associations between serum uric acid levels and the incidence of nonfatal stroke: a nationwide community-based cohort study.
      ,
      • Zhang W.
      • Iso H.
      • Murakami Y.
      • et al.
      Serum uric acid and mortality form cardiovascular disease: EPOCH-Japan study.
      ], indicating that low levels of uric acid, as well as high levels of uric acid, are associated with high risk of cardiovascular events. It has been postulated that antioxidant capability in patients with hypouricemia is decreased with a relative increase in oxidative stress due to the low levels of antioxidant uric acid, resulting in a higher risk of cardiovascular events in hypouricemic patients. Renal hypouricemia is a heterogeneous genetic disorder characterized by impaired uric acid reabsorption and consequent excess urinary excretion of uric acid via loss-of-function mutations of SLC22A/URAT1, resulting in low levels of serum uric acid in patients with renal hypouricemia, who are ideal subjects for determining how endothelial function is affected by excessively low levels of serum uric acid. Recently, Sugihara et al. reported that FMD positively correlated with serum uric acid level in renal hypouricemia patients with serum uric acid of <2.5 mg/dL (mean serum uric acid, 1.14 ± 0.67 mg/dL) [
      • Sugihara S.
      • Hisatome I.
      • Kuwabara M.
      • et al.
      Depletion of uric acid due to SLC22A12 (URAT1) loss-of-function mutation causes endothelial dysfunction in hypouricemia.
      ]. In addition, FMD was significantly lower in hypouricemic patients with serum uric acid of <0.8 mg/dL than in those with serum uric acid of 0.8–2.5 mg/dL. These findings suggest that excessively low levels of serum uric acid are associated with endothelial dysfunction, although there is a possibility that the genetic disorder per se influences endothelial function through alterations of gene expression and function of other uric acid transporters induced by URAT1 mutation. The results of that study are of great interest, supporting the idea that hypouricemia may contribute to endothelial dysfunction, progression of atherosclerosis, and occurrence of cardiovascular events, leading to the J-shaped association between serum uric acid levels and cardiovascular event rates. A recent large-scale cross-sectional study in Japan showed that the prevalence of hypouricemia defined as serum uric acid level ≤2.0 mg/dL was 0.19% [
      • Kuwabara M.
      • Niwa K.
      • Ohtahara A.
      • et al.
      Prevalence and complications of hypouricemia in a general population: a large-scale cross-sectional study in Japan.
      ]. We should pay attention to this population who have a potentially higher risk of cardiovascular events with endothelial dysfunction in clinical practice.

      2. Conclusions

      Uric acid has been shown to be a useful biochemical marker of endothelial function, atherosclerosis, development of cardiovascular risk factors, and occurrence of cardiovascular events. Experimental and clinical studies have shown that endothelial dysfunction is caused by increased ROS generation in the process of purine metabolism catalyzed by XO and have indicated the possibility that XO is a therapeutic target for the prevention of endothelial dysfunction. However, it has not been fully determined whether uric acid per se is an independent causal risk factor of endothelial dysfunction in humans. Although experimental studies have shown that uric acid absorbed into endothelial cells via the activation of uric acid transporters causes endothelial dysfunction, there has been no clinical study showing that treatment with a urate transporter inhibitor improves endothelial function. Considering the antioxidant properties of uric acid, an increase in uric acid levels in patients with cardiovascular risk factors could also be regarded as a compensatory mechanism to counteract the oxidative stress induced under these conditions. Further studies are needed to determine whether uric acid per se is causally associated with endothelial function in humans, especially in patients with cardiovascular risk factors.

      Conflicts of interest

      The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript.

      Financial support

      This study was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan ( 1859081500 and 21590898 ) and a Grant in Aid of Japanese Arteriosclerosis Prevention Fund .

      Author contributions

      Yukihito Higashi and Tatsuya Maruhashi drafting the article and conception of this study; Ichiro Hisatome, and Yasuki Kihara revising the article critically for important intellectual content.

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