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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:
2017 Published by Elsevier Inc. on behalf of National Stroke Association.

Introduction findings in infants with HHcy resulting from inborn me-

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

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

may mediate these effects by inducing oxidative stress, synthesis. Initially, ECs can increase the synthesis and
endothelial dysfunction (ED), and inflammation. release of NO for defending themselves and detoxify HHcy,
which in turn leads to the formation of S-nitroso-
Hyperhomocysteinemia and Atherosclerosis homocysteine, a potent vasodilator. Nevertheless, this
defense mechanism is limited, and chronic exposure to
Homocysteine is a thiol-containing amino acid derived HHcy ultimately causes impaired basal NO production,
from dietary methionine. Dietary methionine is converted radical formation, and subsequent endothelial injury. HHcy
to the methyl donor S-adenosylmethionine and is can also decrease the bioavailability and bioactivity of
demethylated to S-adenosylhomocysteine and homocysteine. NO by the oxidative degradation of NO forming ONOO.9
This explains the observation of a decrease in NO de-
HHcy and Oxidative Stress tection as a result of limited bioavailability rather than
suppressed production. The formation of both S-nitroso-
It has been suggested that oxidative stress is the primary
homocysteine and ONOO modulate vessel function by
biochemical mechanism responsible for HHcy-induced cel-
reducing the amount of active NO availability.
lular injury and dysfunction. Reactive oxygen species (ROS),
including superoxide anion, hydrogen peroxide, and hy-
droxyl radical, are produced during the auto-oxidation HHcy and Inflammation
of homocysteine. The auto-oxidation of HHcy could be Atherosclerosis is a chronic inflammatory disease;
one of the sources of ROS production. In vivo,7,8 HHcy HHcy can promote inflammation.10 In vitro studies have
also decreased bioavailability of nitrogen (NO), result- suggested that HHcy induces several proinflammatory
ing in ED. In addition, decreased bioavailability of NO cytokines production. HHcy has also been shown to in-
also contributes to thrombosis and atherosclerosis because crease expression of monocyte chemotactic protein 1 and
endothelium-derived NO inhibits platelet aggregation and interleukin-8 (IL-8) in cultured ECs, which is known to
leukocyte adhesion. Although there is convincing re- enhance monocyte attachment to the endothelium and
search supporting the results that HHcy-mediated radical their recruitment to the subendothelial cell space, a crit-
production elucidates the pathology of vascular injury, ical step in atherosclerotic lesion development.11 Through
studies have not been able to completely underlie the exact the activation of nuclear factor kappa B (NF-B), a tran-
mechanisms linking HHcy, oxidative stress, and cellular scription factor known to stimulate the production of
or tissue damage. Although there is no direct method to cytokines, chemokines, leukocyte adhesion molecules, and
measure oxidative stress in humans, indirect estimates hemopoietic growth factors, all of which are thought to
support the belief that ROS-mediated damage is via un- lead to vascular inflammation and atherogenesis. 12
derlying molecular mechanism of HHcy-mediated vascular A study by Zhang et al13 provides the first evidence dem-
dysfunction. The inability of the tissue to scavenge harmful onstrating that severe HHcy induces systematic in-
oxidants causes lipid peroxidation, protein modifica- flammation and accelerates atherosclerosis in a novel model
tions, endothelial damage, decreasing ability to synthesize of severe HHcy and hypercholesterolemia, which suggest
NO, limited normal vasodilation, cell death, and altera- that HHcy induces inflammatory monocyte subset dif-
tions in tissue morphology.8 It will be important for patients ferentiation in mice independent of hyperlipidemia, and in
with HHcy to develop specific therapeutic strategies and cultured splenocytes mostly via nicotinamide adenine di-
approaches to treat or regulate oxidative-mediated vas- nucleotide two nucleoside phosphate oxidase-mediated
cular dysfunction. There are no data proving whether oxidant stress, and indicate that HHcy-induced inflam-
vascular dysfunction in human subjects with HHcy is im- matory monocyte subset differentiation may be responsible
proved with antioxidant therapy currently. for the increased risk of cardiovascular and cerebrovas-
cular diseases in HHcy. Studies have found that HHcy
HHcy and Endothelial Dysfunction promotes the activity of NF-B by reducing NF-B protein
nitrosylation, then stimulates the release of inflamma-
HHcy-generated reactive oxygen and nitrogen species
tion factor such as tumor necrosis factor-, interleukin-
evoke damaging molecular effects that underlie vascu-
8, and aggravates the inflammatory response.14
lar dysfunction. HHcy induces ED by altering virtually
every component of NO metabolism, including NOS ex-
HHcy and Smooth Muscle Cell Proliferation
pression, localization, activation, and activity. Most studies
point to Hcy-induced oxidative stress as the important Proliferation of vascular smooth muscle cells (VSMC)
mediator in this process, and treating endothelial cells is a prominent characteristic of atherosclerosis. HHcy can
(ECs) with pathophysiological concentrations of HHcy sig- significantly promote the proliferation of VSMC by pro-
nificantly decreases endothelial nitric oxide synthase (eNOS) moting the expression of adhesion molecules, chemokine,
protein expression in a dose-dependent manner.8 HHcy and the VSMC mitogen.15 Physiological and pathological
has been shown to mediate changes in substrate and co- vascular remodeling involves the breakdown and syn-
factor availability and binding that can disrupt NO thesis of the extracellular matrix, which is initiated by a
group of specialized proteases, matrix metalloproteinase studies suggest that HUA plays a role in the develop-
(MMPs). The mechanisms of HHcy-mediated vascular re- ment and pathogenesis of atherosclerosis, which is
modeling have been proposed, yet the process of vascular biologically active and can stimulate ED, oxidative stress,
rearrangement is still unclear. It has been shown that and inflammation.
HHcy induces the production of ROS and reduces the
bioavailability of NO, the first 2 legs of the Toxic Triad, HUA and ED
which supports previous studies that suggest that HHcy-
Mounting evidence is pointing to ED as one of the major
mediated activation of MMPs is potentiated by oxidative
pathophysiological links between exposure to cardiovascular
stress and by decreased NO bioavailability.16 The process
risk factors and the development of atherosclerotic disease.24
of abnormal vascular remodeling is an underlying com-
ED is commonly associated with reduced NO bioavailability
ponent of many vascular pathologies in which the extra-
and an inability of the endothelium to initiate vasodilation
cellular matrix has gross composition, disorganization, and
in response to vasodilatory stimuli such as acetylcholine
altered geometry.17 Studies have suggested that HHcy
or shear stress. It represents an initial reversible step in
can initiate this process and exert its atherogenic effect
the development of atherogenesis; hence, early clinical
by increasing the expression and activity of latent resi-
identification of ED may become a key tool in the pre-
dent MMPs, by several mechanisms.17 As is already known,
vention or reversal of progression to atherosclerosis.25 Several
HHcy promotes a highly toxic oxidative environment within
mechanisms have been proposed to explain the role of
the vasculature, which can trigger the activation of MMPs.18
uric acid in ED and in the development of hypertension
It has extensively investigated the various signaling
in HUA. First, HUA decreases NO production in lung
pathways associated with the HHcy-mediated MMP ac-
ECs mediated by enhanced L-arginine-arginase enzymat-
tivation and the potential roles of MMPs in several vascular
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
HHcy and Endoplasmic Reticulum Stress
of eNOS mRNA.27 HUA also reduced the interaction
The ER contains numerous molecular chaperones and between eNOS and calmodulin in bovine aortic ECs, which
protein disulfide isomerase to assist in correct protein leads to the inactivation of eNOS.28 Third, HUA blocks
folding. The unfolded protein response, an integrated in- vasorelaxation of aortic artery rings in response to
tracellular signaling pathway that responds to ER stress acetylcholine.29 Choi et al30 first elucidated a novel mech-
by increasing the expression of ER-resident molecular chap- anism of HUA-induced ED, using relatively low uric acid
erones, attenuating global protein translation, and degrading concentrations. Uric acid inhibited insulin-stimulated eNOS
unfolded proteins, will be activated in pathological con- phosphorylation and NO production in ECs at a much
ditions or agents that interfere with proper folding and lower concentration than it suppressed insulin-induced
maturation of proteins. ER stress can induce disordered endothelin 1 expression. HUA increased the mean arterial
lipid metabolism, inflammation, and apoptosis, funda- pressure and suppressed the insulin-induced vasorelaxation,
mental processes that contribute to the development and which were completely recovered by lowering uric acid
progression of atherosclerosis.19 Studies suggest a mech- levels via allopurinol. Consistent with the in vitro data
anism by which homocysteine-induced ER stress causes and blood pressure changes, insulin-stimulated phos-
dysregulation of the endogenous sterol response pathway, phorylation levels of protein kinase B (Akt) and eNOS
leading to increased hepatic biosynthesis and uptake of were decreased in aortas obtained from hyperuricemic
cholesterol and triglycerides, which likely explains the rats and recovered by allopurinol. Thus, this study30 pro-
development and progression of hepatic steatosis and pos- vides evidence that uric acid, at physiological concentrations,
sibly atherosclerotic lesions observed in HHcy.20 Studies induces vascular insulin resistance and ED by inhibiting
have demonstrated that apoptotic cell death induced by the insulin-induced phosphatidylinositol 3-kinase-Akt-
ER stress is dependent on inositol requiring enzyme 1 eNOS signaling pathway, NO production, and consequently,
signaling.21 Furthermore, caspase-3 activation is essen- vasorelaxation. Therefore, this is the first link made between
tial for homocysteine-induced apoptotic cell death.22 uric acid-induced ED and vascular insulin resistance.
Recently, research has shown that ER stress induces in-
flammatory responses.23 The pathways linking ER stress HUA and Oxidative Stress
and inflammation include the production of ROS and the
The progression from ED to atherosclerosis is complex
activation of NF-B through the protein kinase R-like ER
and multifactorial. Oxidative stress appears to be the most
kinase and inositol requiring enzyme 1 pathways.
common underlying mechanism for the development of
ED. Usually, the upregulation of intracellular oxidative
Hyperuricemia and Atherosclerosis
stress and ROS promotes several mechanisms, such as
HUA is common in subjects with cardiovascular disease, the activation of nicotinamide adenine dinucleotide phos-
but is not commonly considered a true risk factor. Recent phate oxidase, NO inactivation, formation of peroxynitrite

(ONOO ), uncoupling of eNOS, stimulation of endothelin in dispute, identification of patients who are most likely
expression, and so on.31 Harmful effects of oxidative stress to benefit from this treatment is a subject of continued
include increasing VSMC proliferation (resulting in thick- investigation. Most randomized intervention trials pub-
ening of the vascular wall), EC apoptosis, and increased lished to date have studied groups with only mildly elevated
expression and activity of MMPs, which are involved in homocysteine levels, thus targeting clinical entities for which
the establishment of an atherosclerotic plaque.32 Reac- the attributable risk of homocysteine is unknown or is
tions of uric acid with oxidants may also produce other likely small compared with other factors. Sex, age, smoking,
radicals that might propagate radical chain reaction and vitamin B-12 and folate deficiency, high plasma triglyc-
oxidative damage to cells. Furthermore, uric acid itself eride, high-density lipoprotein cholesterol, and uric acid
or downstream radicals can engage, as a biologically active concentrations were the major risk factors. Vitamin B-12
proinflammatory factor, intracellular oxidant produc- and folate supplementation, concomitant lifestyle changes,
tion via the ubiquitous nicotinamide adenine dinucleotide including smoking cessation and lipid-lowing treatment,
phosphate oxidase-dependent pathway, resulting in redox- may help to decrease plasma total Hcy. There is also strong
dependent intracellular signaling and, in some conditions, indication that uric acid-lowering therapy conveys ben-
oxidative stress.33 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
HUA and Inflammation
6.0 mg/dL. The two main drugs currently used to lower
There seems to be a causal relationship between oxi- HUA are allopurinol and febuxostat. Febuxostat seems
dative stress and inflammation; in addition, inflammation to be more potent than allopurinol in reducing serum uric
is another common underlying mechanism of ED.34 The acid levels, possibly through a more effective blockade
endothelium controls vascular inflammation by releas- of ROS production38 and inhibition of endothelium-
ing NO under physiological conditions. However, a associated xanthine oxidase,39 and can be safely used even
dysfunctional endothelium will promote ROS genera- in patients with renal impairment without needs of dosage
tion and aggravate vascular inflammation, which is adjustments, as necessary with allopurinol. Therefore, the
detrimental to the vascular system. Oxidative stress may role of HHcy and HUA in the development of ED, re-
amplify the vascular inflammation signaling pathways, garded as beginner of atherosclerosis, should be further
and inflammatory cells increasingly release superoxide.34 studied to dissect out the complex mechanism and eval-
Inflammation is also associated with the overexpression uate on larger scale trials.
of tumor necrosis factor-alpha and IL-1, which pro-
motes leukocyte adherence and migration.35 In addition, Acknowledgment: The authors thank Professor Ning Liu
these inflammatory cytokines induce ECs and leuko- and the Department of Neurology, Clinical Medical College,
cytes to express adhesion molecules, such as vascular cell Lanzhou University, Lanzhou, China.
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
1. Held C, Sumner G, Sheridan P, et al. Correlations between
plasma homocysteine and folate concentrations and
Conclusion and Questions carotid atherosclerosis in high-risk individuals: baseline
data from the Homocysteine and Atherosclerosis
In conclusion, there is increasing evidence that HHcy Reduction Trial (HART). Vasc Med 2008;13:245-253.
and HUA may have a key role in atherosclerosis. Cohen 2. McCully KS. Vascular pathology of homocysteinemia:
et al37 showed that a positive association was found between implications for the pathogenesis of arteriosclerosis. Am
HHcy and HUA serum levels, which was true for both J Pathol 1969;56:111-128.
3. Wald DS, Law M, Morris JK. Homocysteine and
males and females. Therefore, one could speculate that cardiovascular disease: evidence on causality from a
accelerated atherosclerosis might be a consequence of the meta-analysis. BMJ 2002;325:1202-1206.
combined effect of these 2 factors. Numerous epidemio- 4. Homocystein Studies Collaboration. Homocysteine and
logical reports have established HHcy as an independent risk of ischemic heart disease and stroke: a meta-analysis.
risk factor for cardiovascular disease, cerebrovascular disease, JAMA 2002;288:2015-2022.
5. Mutluay R, Deger SM, Bahadir E, et al. Uric acid is an
dementia-type disorders, and so on. Although combined important predictor for hypertensive early atherosclerosis.
folic acid and B-vitamin therapy substantially reduces ho- Adv Ther 2012;29:276-286.
mocysteine levels, results from randomized placebo- 6. Kratz A, Pesce MA, Fink DJ. Laboratory values of clinical
controlled clinical trials testing the effect of vitamin therapy importance. In: Fauci AS, Kasper DL, Longo DL, et al.,
on outcome in these diseases are mixed, but have gen- eds. Harrison textbook of internal medicine. 17th ed.
McGraw Hill Companies, 2008:A1-A16.
erally fallen short of expectations. Thus, although the efficacy 7. Lentz SR, Sobey CG, Piegors DJ, et al. Vascular
of combined folic acid, B6, and B12-vitamin supplemen- dysfunction in monkeys with diet-induced
tation in decreasing circulating homocysteine levels is not hyperhomocyst(e)inemia. J Clin Invest 1996;98:24-29.
8. Steed MM, Tyagi SC. Mechanisms of cardiovascular caspase-3 activation and by regulating pro- and anti-
remodelin in hyperhomocysteinemia. Antioxid Redox apoptotic protein levels. Neuroscience 2005;135:879-886.
Signal 2011;15:1935-1937. 23. Zhang K, Kaufman R. From endoplasmic-reticulum
9. Zhang X, Li H, Jin H, et al. Effects of homocysteine on stress to the inflammatory response. Nature 2008;454:455-
endothelial nitric oxide production. Am J Physiol Renal 462.
Physiol 2000;279:671-678. 24. Yang G, Lucas R, Caldwell R, et al. Novel mechanisms
10. Libby P. Inflammation in atherosclerosis. Nature of endothelial dysfunction in diabetes. J Cardiovasc Dis
2002;420:868-874. Res 2010;1:59-63.
11. Poddar R, Sivasubramanian N, Dibello PM, et al. 25. Chhabra N. Endothelial dysfunctiona predictor of
Homocysteine induces expression and secretion of atherosclerosis, Internet J Med Update 2009;4:33-41.
monocyte chemoattractant protein-1 and interleukin-8 in 26. Zharikov S, Krotova K, Hu H, et al. Uric acid decreases
human aortic endothelial cells: implications for vascular no production and increases arginase activity in cultured
disease. Circulation 2001;103:2717-2723. pulmonary artery endothelial cells. Am J Physiol Cell
12. Zeng XK, Guan YF, Remick DG, et al. Signal pathways Physiol 2008;295:C1183-C1190.
underlying homocysteine-induced production of MCP-1 27. Hong Q, Qi K, Feng Z, et al. Hyperuricemia induces
and IL-8 in cultured human whole blood. Acta Pharmacol endothelial dysfunction via mitochondrial Na/Ca2+
Sin 2005;26:85-91. exchanger-mediated mitochondrial calcium overload. Cell
13. Zhang D, Jiang X, Fang P, et al. Hyperhomocysteinemia Calcium 2012;51:402-410.
promotes inflammatory monocyte generation and 28. Park JH, Jin YM, Hwang S, et al. Uric acid attenuates
accelerates atherosclerosis in transgenic cystathionine nitric oxide production by decreasing the interaction
-synthase deficient mice. Circulation 2009;120:1893- between endothelial nitric oxide synthase and calmodulin
1902. in human umbilical vein endothelial cells: a mechanism
14. Chen Y, Zhao S, Huang B, et al. Probucol and cilostazol for uric acid-induced cardiovascular disease development.
exert a combinatorial anti-atherogenic effect in cholesterol- Nitric Oxide 2013;32:36-42.
fed rabbits. Thromb Res 2013;132:564-571. 29. Papekov I, Pekarov M, Kolrov H, et al. Uric acid
15. Tsai JC, Perrella A, Yoshizumi M, et al. Promotion of modulates vascular endothelial function through the down
vascular smooth muscle cell growth by homocysteine: regulation of nitric oxide production. Free Radic Res
a link to atherosclerosis. Proc Natl Acad Sci USA 2013;47:82-88.
1994;91:6369-6373. 30. Choi Y-J, Yoon Y, Lee K-Y, et al. Uric acid induces
16. Tyagi SC, Smiley LM, Mujumdar VS, et al. Reduction- endothelial dysfunction by vascular insulin resistance
oxidation (redox) and vascular tissue level of associated with the impairment of nitric oxide synthesis.
homocysteine in human coronary atherosclerotic lesions FASEB J Res Commun 2014;28:3201-3202.
and role in vascular ECM remodeling and vascular tone. 31. Frstermann U, Mnzel T. Endothelial nitric oxide
Mol Cell Biochem 1998;81:107-116. synthase in vascular disease: from marvel to menace.
17. Tyagi SC. Physiology and homeostasis of extracellular Circulation 2006;113:1708-1714.
matrix: cardiovascular adaptation and remodeling. 32. Puranik R, Celermajer DS. Smoking and endothelial
Pathophysiology 2000;7:177-182. function. Progr Cardiovasc Dis 2003;45:443-458.
18. Siwik DA, Pagano PJ, Colucci WS. Oxidative stress 33. Sautin YY, Johnson RJ. Uric acid: the oxidantantioxidant
regulates collagen synthesis and matrix metalloproteinase paradox. Nucleosides Nucleotides Nucleic Acids 2010;2:5.
activity in cardiac fibroblasts. Am J Physiol Cell Physiol 34. Karbach S, Wenzel P, Waisman A, et al. eNOS uncoupling
2001;280:53-60. in cardiovascular diseasesthe role of oxidative stress
19. Zhou J, Austin RC. Contributions of hyperhomocysteinemia and inflammation. Curr Pharm Des 2014;20:3579-3594.
to atherosclerosis: causal relationship and potential 35. Barton M. Prevention and endothelial therapy of coronary
mechanisms. Biofactors 2009;35:124-125. International Union artery disease. Curr Opin Pharmacol 2013;13:226-241.
of Biochemistry and Molecular Biology, Inc. 36. Blake GJ, Ridker PM. Novel clinical markers of vascular
20. Werstuck GH, Lentz SR, Dayal S, et al. Homocysteine- wall inflammation. Circ Res 2001;89:763-771.
induced endoplasmic reticulum stress causes dysregulation 37. Cohen E, Levi A, Vecht-Lifshitz SE, et al. Assessment
of the cholesterol and triglyceride biosynthetic pathways. of a possible link between hyperhomocysteinemia and
J Clin Invest 2001;107:1263-1273. hyperuricemia. Invest Med 2015;63:536.
21. Zhang C, Cai Y, Adachi MT, et al. Homocysteine induces 38. Love BL, Barrons R, Veverka A, et al. Urate-lowering
programmed cell death in human vascular endothelial therapy for gout: focus on febuxostat. Pharmacotherapy
cells through activation of the unfolded protein response. 2010;30:594-608.
J Biol Chem 2001;276:35867-35874. 39. Malik Z, Hundley NJ, Romero G, et al. Febuxostat
22. Baydas G, Reiter RJ, Akbulut M, et al. Melatonin inhibits inhibition of endothelial-bound XO: implications for
neural apoptosis induced by homocysteine in hippocampus targeting vascular ROS production. Free Radic Biol Med
of rats via inhibition of cytochrome c translocation and 2011;51:179-184.