ARTICLE IN PRESS

Review Article

Role of Hyperhomocysteinemia and Hyperuricemia in

Pathogenesis of Atherosclerosis

Junjie Zhao, Hailin Chen, Ning Liu, MD, Jun Chen, Youquan Gu,
Jiangjun Chen, and Kui Yang

Background: The mechanisms of hyperhomocysteinemia (HHcy) and hyperurice-

mia (HUA) that promote atherosclerosis were seldom explored and always indefinite.
Therefore, we will discuss some new reviews about the role of HHcy and HUA
in the pathogenesis of atherosclerosis. Methods: This study was conducted by reading
a lot of literature, including basic research and clinical application research. Results:
HHcy is known as an independent risk factor for atherosclerosis. Possible mecha-
nisms for the association between homocysteine and atherosclerosis include stimulating
smooth muscle cell growth, reducing endothelial cell growth and endothelial cell
relaxation, and decreasing synthesis of high-density lipoprotein. HUA causes en-
dothelial dysfunction and thereby increases oxidative stress, inducing vascular smooth
muscle cell proliferation and reducing endothelial nitric oxide bioavailability.
HUA plays a role in the development and pathogenesis of metabolic syndrome,
hypertension, stroke, and atherosclerosis. Conclusions: Accelerated atherosclero-
sis may be a consequence of the combined effect of HHcy and HUA. Key Words:
Hyperhomocysteinemiahyperuricemiaatherosclerosismechanisms.
2017 Published by Elsevier Inc. on behalf of National Stroke Association.

Introduction findings in infants with HHcy resulting from inborn me-

Hyperhomocysteinemia (HHcy) is typically defined as
levels >102mol/L in reported studies.1 The first involve-
ment of HHcy in atherosclerosis was made by McCully
approximately 40 years ago, which is based on pathological
From the Department of Neurology, Zhoukou Central Hospital,
Zhoukou, Henan 466000, China.
Received September 5, 2016; revision received October 1, 2016;
accepted October 10, 2016.
Junjie Zhao and Hailin Chen contributed equally to the paper.
Declaration of Interest: No potential conflict of interest was re-
ported by the authors.
Funding: The authors have declared no specific funding for this
study.
Address correspondence to Ning Liu, MD, Department of
Neurology, Clinical Medical College, Lanzhou University, Lanzhou,
Gansu 730000, China. E-mail: Lnning1957@sina.com.
1052-3057/$ - see front matter
2017 Published by Elsevier Inc. on behalf of National Stroke
Association.
https://doi.org/10.1016/j.jstrokecerebrovasdis.2016.10.012
tabolism deficiency.2 A large number of epidemiological
studies suggest that increased homocysteine level is an
independent risk factor for vascular diseases, including
stroke.3,4 HHcy-induced oxidative stress, endothelium dys-
function, inflammation, smooth muscle cell proliferation,
and endoplasmic reticulum (ER) stress have been con-
sidered to play an important role in the pathogenesis of
atherosclerosis.
Uric acid, the end product of purine catabolism in
humans, is known as an antioxidant. Several studies suggest
serum uric acid levels have an association with surrogate
markers of atherosclerosis. In particular, there is evidence
that hyperuricemia (HUA) has an independent effect on
atherosclerosis, which has a direct effect on key processes
involved in endothelium function and vascular remodeling.5
HUA is defined as greater than 7.0 mg/dL for men and
greater than 5.6 mg/dL for women.6 HUA is currently
suggested to significantly modulate the physiological func-
tions of various cells, particularly vessel endothelium, which

Journal of Stroke and Cerebrovascular Diseases, Vol. , No. (), 2017: pp 1

 ARTICLE IN PRESS
2 J. ZHAO ET AL.
may mediate these effects by inducing oxidative stress,
endothelial dysfunction (ED), and inflammation.
Hyperhomocysteinemia and Atherosclerosis
Homocysteine is a thiol-containing amino acid derived
from dietary methionine. Dietary methionine is converted
to the methyl donor S-adenosylmethionine and is
demethylated to S-adenosylhomocysteine and homocysteine.
HHcy and Oxidative Stress
It has been suggested that oxidative stress is the primary
biochemical mechanism responsible for HHcy-induced cel-
lular injury and dysfunction. Reactive oxygen species (ROS),
including superoxide anion, hydrogen peroxide, and hy-
droxyl radical, are produced during the auto-oxidation
of homocysteine. The auto-oxidation of HHcy could be
one of the sources of ROS production. In vivo,7,8 HHcy
also decreased bioavailability of nitrogen (NO), result-
ing in ED. In addition, decreased bioavailability of NO
also contributes to thrombosis and atherosclerosis because
endothelium-derived NO inhibits platelet aggregation and
leukocyte adhesion. Although there is convincing re-
search supporting the results that HHcy-mediated radical
production elucidates the pathology of vascular injury,
studies have not been able to completely underlie the exact
mechanisms linking HHcy, oxidative stress, and cellular
or tissue damage. Although there is no direct method to
measure oxidative stress in humans, indirect estimates
support the belief that ROS-mediated damage is via un-
derlying molecular mechanism of HHcy-mediated vascular
dysfunction. The inability of the tissue to scavenge harmful
oxidants causes lipid peroxidation, protein modifica-
tions, endothelial damage, decreasing ability to synthesize
NO, limited normal vasodilation, cell death, and altera-
tions in tissue morphology.8 It will be important for patients
with HHcy to develop specific therapeutic strategies and
approaches to treat or regulate oxidative-mediated vas-
cular dysfunction. There are no data proving whether
vascular dysfunction in human subjects with HHcy is im-
proved with antioxidant therapy currently.
HHcy and Endothelial Dysfunction
HHcy-generated reactive oxygen and nitrogen species
evoke damaging molecular effects that underlie vascu-
lar dysfunction. HHcy induces ED by altering virtually
every component of NO metabolism, including NOS ex-
pression, localization, activation, and activity. Most studies
point to Hcy-induced oxidative stress as the important
mediator in this process, and treating endothelial cells
(ECs) with pathophysiological concentrations of HHcy sig-
nificantly decreases endothelial nitric oxide synthase (eNOS)
protein expression in a dose-dependent manner.8 HHcy
has been shown to mediate changes in substrate and co-
factor availability and binding that can disrupt NO
synthesis. Initially, ECs can increase the synthesis and
release of NO for defending themselves and detoxify HHcy,
which in turn leads to the formation of S-nitroso-
homocysteine, a potent vasodilator. Nevertheless, this
defense mechanism is limited, and chronic exposure to
HHcy ultimately causes impaired basal NO production,
radical formation, and subsequent endothelial injury. HHcy
can also decrease the bioavailability and bioactivity of
NO by the oxidative degradation of NO forming ONOO.9
This explains the observation of a decrease in NO de-
tection as a result of limited bioavailability rather than
suppressed production. The formation of both S-nitroso-
homocysteine and ONOO modulate vessel function by
reducing the amount of active NO availability.
HHcy and Inflammation
Atherosclerosis is a chronic inflammatory disease;
HHcy can promote inflammation.10 In vitro studies have
suggested that HHcy induces several proinflammatory
cytokines production. HHcy has also been shown to in-
crease expression of monocyte chemotactic protein 1 and
interleukin-8 (IL-8) in cultured ECs, which is known to
enhance monocyte attachment to the endothelium and
their recruitment to the subendothelial cell space, a crit-
ical step in atherosclerotic lesion development.11 Through
the activation of nuclear factor kappa B (NF-B), a tran-
scription factor known to stimulate the production of
cytokines, chemokines, leukocyte adhesion molecules, and
hemopoietic growth factors, all of which are thought to
lead to vascular inflammation and atherogenesis. 12
A study by Zhang et al13 provides the first evidence dem-
onstrating that severe HHcy induces systematic in-
flammation and accelerates atherosclerosis in a novel model
of severe HHcy and hypercholesterolemia, which suggest
that HHcy induces inflammatory monocyte subset dif-
ferentiation in mice independent of hyperlipidemia, and in
cultured splenocytes mostly via nicotinamide adenine di-
nucleotide two nucleoside phosphate oxidase-mediated
oxidant stress, and indicate that HHcy-induced inflam-
matory monocyte subset differentiation may be responsible
for the increased risk of cardiovascular and cerebrovas-
cular diseases in HHcy. Studies have found that HHcy
promotes the activity of NF-B by reducing NF-B protein
nitrosylation, then stimulates the release of inflamma-
tion factor such as tumor necrosis factor-, interleukin-
8, and aggravates the inflammatory response.14
HHcy and Smooth Muscle Cell Proliferation
Proliferation of vascular smooth muscle cells (VSMC)
is a prominent characteristic of atherosclerosis. HHcy can
significantly promote the proliferation of VSMC by pro-
moting the expression of adhesion molecules, chemokine,
and the VSMC mitogen.15 Physiological and pathological
vascular remodeling involves the breakdown and syn-
thesis of the extracellular matrix, which is initiated by a
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ROLE OF HYPERHOMOCYSTEINEMIA AND HYPERURICEMIA
group of specialized proteases, matrix metalloproteinase
(MMPs). The mechanisms of HHcy-mediated vascular re-
modeling have been proposed, yet the process of vascular
rearrangement is still unclear. It has been shown that
HHcy induces the production of ROS and reduces the
bioavailability of NO, the first 2 legs of the Toxic Triad,
which supports previous studies that suggest that HHcy-
mediated activation of MMPs is potentiated by oxidative
stress and by decreased NO bioavailability.16 The process
of abnormal vascular remodeling is an underlying com-
ponent of many vascular pathologies in which the extra-
cellular matrix has gross composition, disorganization, and
altered geometry.17 Studies have suggested that HHcy
can initiate this process and exert its atherogenic effect
by increasing the expression and activity of latent resi-
dent MMPs, by several mechanisms.17 As is already known,
HHcy promotes a highly toxic oxidative environment within
the vasculature, which can trigger the activation of MMPs.18
It has extensively investigated the various signaling
pathways associated with the HHcy-mediated MMP ac-
tivation and the potential roles of MMPs in several vascular
pathologies.
HHcy and Endoplasmic Reticulum Stress
The ER contains numerous molecular chaperones and
protein disulfide isomerase to assist in correct protein
folding. The unfolded protein response, an integrated in-
tracellular signaling pathway that responds to ER stress
by increasing the expression of ER-resident molecular chap-
erones, attenuating global protein translation, and degrading
unfolded proteins, will be activated in pathological con-
ditions or agents that interfere with proper folding and
maturation of proteins. ER stress can induce disordered
lipid metabolism, inflammation, and apoptosis, funda-
mental processes that contribute to the development and
progression of atherosclerosis.19 Studies suggest a mech-
anism by which homocysteine-induced ER stress causes
dysregulation of the endogenous sterol response pathway,
leading to increased hepatic biosynthesis and uptake of
cholesterol and triglycerides, which likely explains the
development and progression of hepatic steatosis and pos-
sibly atherosclerotic lesions observed in HHcy.20 Studies
have demonstrated that apoptotic cell death induced by
ER stress is dependent on inositol requiring enzyme 1
signaling.21 Furthermore, caspase-3 activation is essen-
tial for homocysteine-induced apoptotic cell death.22
Recently, research has shown that ER stress induces in-
flammatory responses.23 The pathways linking ER stress
and inflammation include the production of ROS and the
activation of NF-B through the protein kinase R-like ER
kinase and inositol requiring enzyme 1 pathways.
Hyperuricemia and Atherosclerosis
HUA is common in subjects with cardiovascular disease,
but is not commonly considered a true risk factor. Recent
3
studies suggest that HUA plays a role in the develop-
ment and pathogenesis of atherosclerosis, which is
biologically active and can stimulate ED, oxidative stress,
and inflammation.
HUA and ED
Mounting evidence is pointing to ED as one of the major
pathophysiological links between exposure to cardiovascular
risk factors and the development of atherosclerotic disease.24
ED is commonly associated with reduced NO bioavailability
and an inability of the endothelium to initiate vasodilation
in response to vasodilatory stimuli such as acetylcholine
or shear stress. It represents an initial reversible step in
the development of atherogenesis; hence, early clinical
identification of ED may become a key tool in the pre-
vention or reversal of progression to atherosclerosis.25 Several
mechanisms have been proposed to explain the role of
uric acid in ED and in the development of hypertension
in HUA. First, HUA decreases NO production in lung
ECs mediated by enhanced L-arginine-arginase enzymat-
ic activity.26 Second, HUA decreases eNOS expression and
NO production in human umbilical vein endothelial cell
via C-reactive protein or calcium ion-induced instability
of eNOS mRNA.27 HUA also reduced the interaction
between eNOS and calmodulin in bovine aortic ECs, which
leads to the inactivation of eNOS.28 Third, HUA blocks
vasorelaxation of aortic artery rings in response to
acetylcholine.29 Choi et al30 first elucidated a novel mech-
anism of HUA-induced ED, using relatively low uric acid
concentrations. Uric acid inhibited insulin-stimulated eNOS
phosphorylation and NO production in ECs at a much
lower concentration than it suppressed insulin-induced
endothelin 1 expression. HUA increased the mean arterial
pressure and suppressed the insulin-induced vasorelaxation,
which were completely recovered by lowering uric acid
levels via allopurinol. Consistent with the in vitro data
and blood pressure changes, insulin-stimulated phos-
phorylation levels of protein kinase B (Akt) and eNOS
were decreased in aortas obtained from hyperuricemic
rats and recovered by allopurinol. Thus, this study30 pro-
vides evidence that uric acid, at physiological concentrations,
induces vascular insulin resistance and ED by inhibiting
the insulin-induced phosphatidylinositol 3-kinase-Akt-
eNOS signaling pathway, NO production, and consequently,
vasorelaxation. Therefore, this is the first link made between
uric acid-induced ED and vascular insulin resistance.
HUA and Oxidative Stress
The progression from ED to atherosclerosis is complex
and multifactorial. Oxidative stress appears to be the most
common underlying mechanism for the development of
ED. Usually, the upregulation of intracellular oxidative
stress and ROS promotes several mechanisms, such as
the activation of nicotinamide adenine dinucleotide phos-
phate oxidase, NO inactivation, formation of peroxynitrite
 ARTICLE IN PRESS
4 J. ZHAO ET AL.
(ONOO ), uncoupling of eNOS, stimulation of endothelin
expression, and so on.31 Harmful effects of oxidative stress
include increasing VSMC proliferation (resulting in thick-
ening of the vascular wall), EC apoptosis, and increased
expression and activity of MMPs, which are involved in
the establishment of an atherosclerotic plaque.32 Reac-
tions of uric acid with oxidants may also produce other
radicals that might propagate radical chain reaction and
oxidative damage to cells. Furthermore, uric acid itself
or downstream radicals can engage, as a biologically active
proinflammatory factor, intracellular oxidant produc-
tion via the ubiquitous nicotinamide adenine dinucleotide
phosphate oxidase-dependent pathway, resulting in redox-
dependent intracellular signaling and, in some conditions,
oxidative stress.33
HUA and Inflammation
There seems to be a causal relationship between oxi-
dative stress and inflammation; in addition, inflammation
is another common underlying mechanism of ED.34 The
endothelium controls vascular inflammation by releas-
ing NO under physiological conditions. However, a
dysfunctional endothelium will promote ROS genera-
tion and aggravate vascular inflammation, which is
detrimental to the vascular system. Oxidative stress may
amplify the vascular inflammation signaling pathways,
and inflammatory cells increasingly release superoxide.34
Inflammation is also associated with the overexpression
of tumor necrosis factor-alpha and IL-1, which pro-
motes leukocyte adherence and migration.35 In addition,
these inflammatory cytokines induce ECs and leuko-
cytes to express adhesion molecules, such as vascular cell
adhesion molecules and intercellular adhesion mol-
ecules, monocyte chemotactic protein-1, E-selectin, P-selectin,
and IL-6, resulting in a worsening of ED.36
Conclusion and Questions
In conclusion, there is increasing evidence that HHcy
and HUA may have a key role in atherosclerosis. Cohen
et al37 showed that a positive association was found between
HHcy and HUA serum levels, which was true for both
males and females. Therefore, one could speculate that
accelerated atherosclerosis might be a consequence of the
combined effect of these 2 factors. Numerous epidemio-
logical reports have established HHcy as an independent
risk factor for cardiovascular disease, cerebrovascular disease,
dementia-type disorders, and so on. Although combined
folic acid and B-vitamin therapy substantially reduces ho-
mocysteine levels, results from randomized placebo-
controlled clinical trials testing the effect of vitamin therapy
on outcome in these diseases are mixed, but have gen-
erally fallen short of expectations. Thus, although the efficacy
of combined folic acid, B6, and B12-vitamin supplemen-
tation in decreasing circulating homocysteine levels is not
in dispute, identification of patients who are most likely
to benefit from this treatment is a subject of continued
investigation. Most randomized intervention trials pub-
lished to date have studied groups with only mildly elevated
homocysteine levels, thus targeting clinical entities for which
the attributable risk of homocysteine is unknown or is
likely small compared with other factors. Sex, age, smoking,
vitamin B-12 and folate deficiency, high plasma triglyc-
eride, high-density lipoprotein cholesterol, and uric acid
concentrations were the major risk factors. Vitamin B-12
and folate supplementation, concomitant lifestyle changes,
including smoking cessation and lipid-lowing treatment,
may help to decrease plasma total Hcy. There is also strong
indication that uric acid-lowering therapy conveys ben-
eficial effects in the management of several cardiovascular
and metabolic diseases. With regard to pharmacological
therapy, the goal is to keep serum uric acid levels below
6.0 mg/dL. The two main drugs currently used to lower
HUA are allopurinol and febuxostat. Febuxostat seems
to be more potent than allopurinol in reducing serum uric
acid levels, possibly through a more effective blockade
of ROS production38 and inhibition of endothelium-
associated xanthine oxidase,39 and can be safely used even
in patients with renal impairment without needs of dosage
adjustments, as necessary with allopurinol. Therefore, the
role of HHcy and HUA in the development of ED, re-
garded as beginner of atherosclerosis, should be further
studied to dissect out the complex mechanism and eval-
uate on larger scale trials.
Acknowledgment: The authors thank Professor Ning Liu
and the Department of Neurology, Clinical Medical College,
Lanzhou University, Lanzhou, China.
References
1. Held C, Sumner G, Sheridan P, et al. Correlations between
plasma homocysteine and folate concentrations and
carotid atherosclerosis in high-risk individuals: baseline
data from the Homocysteine and Atherosclerosis
Reduction Trial (HART). Vasc Med 2008;13:245-253.
2. McCully KS. Vascular pathology of homocysteinemia:
implications for the pathogenesis of arteriosclerosis. Am
J Pathol 1969;56:111-128.
3. Wald DS, Law M, Morris JK. Homocysteine and
cardiovascular disease: evidence on causality from a
meta-analysis. BMJ 2002;325:1202-1206.
4. Homocystein Studies Collaboration. Homocysteine and
risk of ischemic heart disease and stroke: a meta-analysis.
JAMA 2002;288:2015-2022.
5. Mutluay R, Deger SM, Bahadir E, et al. Uric acid is an
important predictor for hypertensive early atherosclerosis.
Adv Ther 2012;29:276-286.
6. Kratz A, Pesce MA, Fink DJ. Laboratory values of clinical
importance. In: Fauci AS, Kasper DL, Longo DL, et al.,
eds. Harrison textbook of internal medicine. 17th ed.
McGraw Hill Companies, 2008:A1-A16.
7. Lentz SR, Sobey CG, Piegors DJ, et al. Vascular
dysfunction in monkeys with diet-induced
hyperhomocyst(e)inemia. J Clin Invest 1996;98:24-29.
 ARTICLE IN PRESS
ROLE OF HYPERHOMOCYSTEINEMIA AND HYPERURICEMIA
8. Steed MM, Tyagi SC. Mechanisms of cardiovascular
remodelin in hyperhomocysteinemia. Antioxid Redox
Signal 2011;15:1935-1937.
9. Zhang X, Li H, Jin H, et al. Effects of homocysteine on
endothelial nitric oxide production. Am J Physiol Renal
Physiol 2000;279:671-678.
10. Libby P. Inflammation in atherosclerosis. Nature
2002;420:868-874.
11. Poddar R, Sivasubramanian N, Dibello PM, et al.
Homocysteine induces expression and secretion of
monocyte chemoattractant protein-1 and interleukin-8 in
human aortic endothelial cells: implications for vascular
disease. Circulation 2001;103:2717-2723.
12. Zeng XK, Guan YF, Remick DG, et al. Signal pathways
underlying homocysteine-induced production of MCP-1
and IL-8 in cultured human whole blood. Acta Pharmacol
Sin 2005;26:85-91.
13. Zhang D, Jiang X, Fang P, et al. Hyperhomocysteinemia
promotes inflammatory monocyte generation and
accelerates atherosclerosis in transgenic cystathionine
-synthase deficient mice. Circulation 2009;120:1893-
1902.
14. Chen Y, Zhao S, Huang B, et al. Probucol and cilostazol
exert a combinatorial anti-atherogenic effect in cholesterol-
fed rabbits. Thromb Res 2013;132:564-571.
15. Tsai JC, Perrella A, Yoshizumi M, et al. Promotion of
vascular smooth muscle cell growth by homocysteine:
a link to atherosclerosis. Proc Natl Acad Sci USA
1994;91:6369-6373.
16. Tyagi SC, Smiley LM, Mujumdar VS, et al. Reduction-
oxidation (redox) and vascular tissue level of
homocysteine in human coronary atherosclerotic lesions
and role in vascular ECM remodeling and vascular tone.
Mol Cell Biochem 1998;81:107-116.
17. Tyagi SC. Physiology and homeostasis of extracellular
matrix: cardiovascular adaptation and remodeling.
Pathophysiology 2000;7:177-182.
18. Siwik DA, Pagano PJ, Colucci WS. Oxidative stress
regulates collagen synthesis and matrix metalloproteinase
activity in cardiac fibroblasts. Am J Physiol Cell Physiol
2001;280:53-60.
19. Zhou J, Austin RC. Contributions of hyperhomocysteinemia
to atherosclerosis: causal relationship and potential
mechanisms. Biofactors 2009;35:124-125. International Union
of Biochemistry and Molecular Biology, Inc.
20. Werstuck GH, Lentz SR, Dayal S, et al. Homocysteine-
induced endoplasmic reticulum stress causes dysregulation
of the cholesterol and triglyceride biosynthetic pathways.
J Clin Invest 2001;107:1263-1273.
21. Zhang C, Cai Y, Adachi MT, et al. Homocysteine induces
programmed cell death in human vascular endothelial
cells through activation of the unfolded protein response.
J Biol Chem 2001;276:35867-35874.
22. Baydas G, Reiter RJ, Akbulut M, et al. Melatonin inhibits
neural apoptosis induced by homocysteine in hippocampus
of rats via inhibition of cytochrome c translocation and
5
caspase-3 activation and by regulating pro- and anti-
apoptotic protein levels. Neuroscience 2005;135:879-886.
23. Zhang K, Kaufman R. From endoplasmic-reticulum
stress to the inflammatory response. Nature 2008;454:455-
462.
24. Yang G, Lucas R, Caldwell R, et al. Novel mechanisms
of endothelial dysfunction in diabetes. J Cardiovasc Dis
Res 2010;1:59-63.
25. Chhabra N. Endothelial dysfunctiona predictor of
atherosclerosis, Internet J Med Update 2009;4:33-41.
26. Zharikov S, Krotova K, Hu H, et al. Uric acid decreases
no production and increases arginase activity in cultured
pulmonary artery endothelial cells. Am J Physiol Cell
Physiol 2008;295:C1183-C1190.
27. Hong Q, Qi K, Feng Z, et al. Hyperuricemia induces
endothelial dysfunction via mitochondrial Na/Ca2+
exchanger-mediated mitochondrial calcium overload. Cell
Calcium 2012;51:402-410.
28. Park JH, Jin YM, Hwang S, et al. Uric acid attenuates
nitric oxide production by decreasing the interaction
between endothelial nitric oxide synthase and calmodulin
in human umbilical vein endothelial cells: a mechanism
for uric acid-induced cardiovascular disease development.
Nitric Oxide 2013;32:36-42.
29. Papekov I, Pekarov M, Kolrov H, et al. Uric acid
modulates vascular endothelial function through the down
regulation of nitric oxide production. Free Radic Res
2013;47:82-88.
30. Choi Y-J, Yoon Y, Lee K-Y, et al. Uric acid induces
endothelial dysfunction by vascular insulin resistance
associated with the impairment of nitric oxide synthesis.
FASEB J Res Commun 2014;28:3201-3202.
31. Frstermann U, Mnzel T. Endothelial nitric oxide
synthase in vascular disease: from marvel to menace.
Circulation 2006;113:1708-1714.
32. Puranik R, Celermajer DS. Smoking and endothelial
function. Progr Cardiovasc Dis 2003;45:443-458.
33. Sautin YY, Johnson RJ. Uric acid: the oxidantantioxidant
paradox. Nucleosides Nucleotides Nucleic Acids 2010;2:5.
34. Karbach S, Wenzel P, Waisman A, et al. eNOS uncoupling
in cardiovascular diseasesthe role of oxidative stress
and inflammation. Curr Pharm Des 2014;20:3579-3594.
35. Barton M. Prevention and endothelial therapy of coronary
artery disease. Curr Opin Pharmacol 2013;13:226-241.
36. Blake GJ, Ridker PM. Novel clinical markers of vascular
wall inflammation. Circ Res 2001;89:763-771.
37. Cohen E, Levi A, Vecht-Lifshitz SE, et al. Assessment
of a possible link between hyperhomocysteinemia and
hyperuricemia. Invest Med 2015;63:536.
38. Love BL, Barrons R, Veverka A, et al. Urate-lowering
therapy for gout: focus on febuxostat. Pharmacotherapy
2010;30:594-608.
39. Malik Z, Hundley NJ, Romero G, et al. Febuxostat
inhibition of endothelial-bound XO: implications for
targeting vascular ROS production. Free Radic Biol Med
2011;51:179-184.