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1866 Regular Article Biol. Pharm. Bull. 37(12) 18661871 (2014) Vol. 37, No. 12

Is Hyperuricemia a Risk Factor for Arteriosclerosis? Uric Acid and

Arteriosclerosis in Apolipoprotein E-Decient Mice
Hirokazu Wakuda,a,b Shinya Uchida,c Masahiko Ikeda,d Masaki Tabuchi,e Yasumitsu Akahoshi, f
Kazumasa Shinozuka,a and Shizuo Yamada*,g
a
Department of Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Womens
University; 1168 Koshien, Kyuban-cho, Nishinomiya 6638179, Japan: bDepartment of Pharmacokinetics and
Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka; cDepartment of Pharmacy
Practice and Science, School of Pharmaceutical Sciences, University of Shizuoka; gCenter for Pharma-Food
Research (CPFR), Graduate School of Pharmaceutical Sciences, University of Shizuoka; 521 Yada, Suruga-ku,
Shizuoka 4228526, Japan: dCollege of Environment and Disaster Research, Fuji Tokoha University; 325 Obuchi,
Fuji, Shizuoka 4170801, Japan: eDepartment of Pharmacology, Kinki University School of Medicine; and fLife
Science Research Institute, Kinki University School of Medicine; 341 Kowakae, Higashiosaka, Osaka 5778502,
Japan.
Received March 3, 2014; accepted September 17, 2014

Although hyperlipidemia, high blood pressure, and diabetes increase the risk of arteriosclerosis, it is
not clear whether hyperuricemia increases the risk of arteriosclerosis or not. We examined the effects of
uric acid and curative drugs for hyperuricemia on atherosclerosis-susceptible C57BL/6J apolipoprotein
E-decient (apoE/) mice. Male apoE/ mice (age: 6 weeks) were fed a normal diet (normal diet group)
or a uric acid-enriched diet. Mice fed the uric acid-enriched diet were divided into three groups and ad-
ministered a drinking vehicle (high uric acid diet group), allopurinol (20 mgkg1d1), or benzbromarone
(20 mgkg1d1) for 10 weeks. Serum uric acid concentrations were higher in the high uric acid diet group
than in the normal diet group, and concentrations in the allopurinol and benzbromarone groups were lower
than in the high uric acid diet group. Serum total cholesterol and triglyceride levels were lower in the allo-
purinol group than in the high uric acid diet group. Oxidative stress was lower in the benzbromarone group
than in the high uric acid diet group. Atherosclerotic lesion areas were smaller in the allopurinol and ben-
zbromarone groups than in the high uric acid diet group. Thus, hyperuricemia may not be an independent
risk factor for arteriosclerosis; however, the administration of allopurinol and benzbromarone prevented the
development of atherosclerosis in apoE/ mice fed a uric acid-enriched diet. The anti-atherosclerotic effect
was in part due to lower total cholesterol and oxidative stress in the serum. Other possible mechanisms un-
derlying this effect should be investigated.
Key words hyperuricemia; atherosclerosis; apolipoprotein E-decient mouse; allopurinol; benzbromarone

Uric acid is the nal product of purine metabolism in hu-

mans. The role of uric acid in cardiovascular disease remains
unclear. Although some epidemiological studies have shown
that hyperuricemia (gout) is an independent risk factor for
cardiovascular disease,13) others have suggested that this as-
sociation is confounded by the coexistence of conditions such
as hypertension, obesity, hyperlipidemia, and diabetes mel-
litus, all of which are known to be independent risk factors for
atherosclerosis.46)
Hyperuricemia is the presence of high levels of uric acid
in the blood (serum urate >7 mgdL1). It is classied into
three types: increased production of uric acid, decreased ex-
cretion of uric acid, and mixed type.7) Uric acid is produced Fig. 1. Biosynthesis of Uric Acid and the Site of Allopurinol and
Benzbromarone Action
by xanthine oxidase from xanthine and hypoxanthine (Fig. 1).
Allopurinol and its major active metabolite oxypurinol, which
has a much longer half-life than allopurinol and is primarily uric acid were used to elevate serum uric acid levels in apoli-
eliminated by renal excretion, inhibit the activity of xanthine poprotein E-decient (apoE/) mice.
oxidase and suppress uric acid generation upstream.8) Benz- ApoE/ mice are generated by targeted inactivation of the
bromarone is a uricosuric agent that blocks tubular reabsorp- apolipoprotein E gene and are widely used for atherosclerosis
tion of uric acid. In most mammals, uric acid is further me- studies.9,10) Lesion formation in this mouse model is similar to
tabolized to allantoin by the enzyme uricase. In order to study that in well-established larger animal models of atherosclero-
hyperuricemia in an animal model, uricase can be blocked by sis and in humans.11) Therefore, it is useful for studying the
selective inhibitors. Potassium oxonate is a well-known inhibi- pathogenesis of atherosclerosis as well as potential therapies.12)
tor of uricase. In this study, 5% potassium oxonate and 2.5% In this study, the anti-atherosclerotic effects of allopurinol
and benzbromarone were examined in hyperuricemic apoE/
The authors declare no conflict of interest. mice.
 To whom correspondence should be addressed. e-mail: yamada@u-shizuoka-ken.ac.jp
* 2014 The Pharmaceutical Society of Japan
December 20141867
MATERIALS AND METHODS
Materials Allopurinol, benzbromarone, uric acid, and
potassium oxonate were obtained from Sigma-Aldrich Co.
(St. Louis, MO, U.S.A.). Other chemicals of analytical reagent
grade were purchased from Wako Pure Chemical Industries,
Ltd. (Osaka, Japan).
Animals and Treatments Animals were handled hu-
manely in accordance with the Guidelines for the Care and
Use of Laboratory Animals of the University of Shizuoka.
The experimental protocol and animal use procedures were
approved by the Committee of the University of Shizuoka.
ApoE/ mice were purchased from Jackson Laboratories (Bar
Harbor, ME, U.S.A.) and bred in our laboratory under specic
pathogen-free conditions. Male apoE/ mice at 6 weeks of
age were divided into four groups. The normal diet group was
fed a normal diet (CRF-1; Oriental Yeast, Tokyo, Japan) and
drinking vehicle (0.5% carboxymethyl cellulose and 1% etha-
nol). The high uric acid diet, allopurinol, and benzbromarone
groups were fed a uric acid-enriched diet (CRF-1 contain-
ing 5% potassium oxonate and 2.5% uric acid) and drink-
ing vehicle, allopurinol (20 mgkg1d1), or benzbromarone 0.08 mg/100 mL H2O2, and is equivalent to the hydroperoxide
(20 mgkg1d1), respectively, for 10 weeks. Body weight and concentration.
serum total cholesterol (TC) and triglyceride (TG) concentra-
tions were measured every 2 weeks during the experimental
period. At the end of the experiment, when mice were 16
weeks of age, they were anesthetized with diethyl ether and
blood was collected from the abdominal aorta. The heart was
perfused with phosphate-buffered saline and 10% formalin
neutral buffer solution (pH 7.07.5), excised with the aortic
arch, and placed in 10% formalin neutral buffer solution for
2 weeks.
Measurement of Serum Uric Acid Concentrations The
blood was allowed to stand at room temperature for 1 h. The
serum was obtained by centrifugation at 1000g for 10 min at
4C and kept at 80C until analysis. Serum samples (30 L) by a post-hoc Dunnett's test or by two-way ANOVA followed
were mixed with 0.3 mol/L perchloric acid (1.0 mL). The sam-
ples were kept on ice for 30 min. After vortexing, the samples
were centrifuged at 3000g for 10 min. The supernatants
(300 L) were then mixed with an equal volume of 0.2 mol/L
disodium phosphate and ltered through 0.45-m Millipore
lters (Millipore, Bedford, MA, U.S.A.). A 50-L sample was
injected into an HPLC unit tted with a pump (LC-20ADVP;
Shimadzu, Kyoto, Japan), autosampler (SIL-20AC; Shimadzu),
and system controller (CBM-20A; Shimadzu). Separations
were performed at room temperature with a 4.6150 mm
column [Phenomenex Luna 3u C18 (2) 100A; Shimadzu]. Ab-
sorbance was monitored at 284 nm with an ultraviolet variable
wavelength detector (SPD-20AVP; Shimadzu). The flow rate
was 1.0 mL/min and the mobile phase buffer was phosphoric
acid/methanol (74 mmol/L, pH 2.2).
Measurement of Serum TC and TG Concentrations
Serum TC and TG concentrations were measured with com-
mercial kits (Cholesterol E-test and Triglyceride E-test; Wako
Pure Chemical Industries, Ltd.).
Measurement of Oxidative Stress To monitor oxidative
stress, including hydroperoxides, serum levels of derivatives
of reactive oxygen metabolites (d-ROMs) were determined
using a free radical analytical system (FRAS4; Wismerll,
Tokyo, Japan). This test measured the equilibrium between
free radical production and antioxidant defense. Hydroper-
Fig. 2. Changes in Body Weight: apoE/ Mice Fed a Normal
Diet+Vehicle (), a High Uric Acid Diet+Vehicle (), a High Uric
Acid Diet+Allopurinol (20 mgkg1d1, ), or a High Uric Acid
Diet+Benzbromarone (20 mgkg1d1, ) for 10 Weeks
Each point represents the meanS.E. of 7 to 10 mice.
oxides are converted into radicals that can oxidize a chro-
mogenic substrate (N,N-diethyl-para-phenylenediamine) and
be detected by spectrophotometric analysis at 505 nm. In
this method, 1 unit (Carratelli units: U. CARR) represents
Histologic Analysis of Atherosclerotic Lesions The for-
malin-xed hearts were cut horizontally just under the atrium.
The aortic root with the top of the heart was embedded in par-
afn and serially sectioned at 5-m intervals. Cross sections
were taken at the level of the aortic valves and stained with
hematoxylin and eosin. The area of the atherosclerotic lesions
in the hearts of the mice was measured with image analysis
software (Micro Analyzer; Japan Poladigital, Tokyo, Japan).
Atherosclerotic lesions were calculated as the sum of the le-
sion area across four cross-sections.
Statistical Analysis All values represent the mean
S.E.M. Results were analyzed by one-way ANOVA followed
by a Bonferroni post-test. The signicance level was set at
p<0.05. Statistical analyses were performed in GraphPad
Prism 4.03 software (GraphPad Software, La Jolla, CA,
U.S.A.).
RESULTS
No signicant difference in body weight was observed
between the normal diet group and the other groups (Fig. 2).
Food intake was approximately 4 g/d per mouse throughout
the experiment in all groups (data not shown). Serum uric acid
concentrations in the high uric acid diet group were 3.2-fold
and 2.3-fold higher than in the normal diet group when the
mice were 11 and 16 weeks of age (Fig. 3). In addition, serum
uric acid in the allopurinol and benzbromarone groups was
signicantly lower than in the high uric acid diet group and
similar to the normal diet group (Fig. 3). Serum TC concentra-
tions were 37%, 47%, and 44% lower in the allopurinol group
than in the high uric acid diet group at 10, 14, and 16 weeks of
age (Fig. 4A). Serum TG concentrations were 2246% lower
in the allopurinol group than in the high uric acid diet group
after 10 weeks of age (Fig. 4B). There was no signicant dif-
ference in the serum TC and TG concentrations between the
normal, high uric acid, and benzbromarone groups during
the experimental period (Figs. 4A, B). Oxidative stress was
1868 Vol. 37, No. 12

Fig. 3. Serum Concentrations of Uric Acid in apoE/ Mice Fed a Normal Diet+Vehicle (), a High Uric Acid Diet+Vehicle (), a High Uric Acid
Diet+Allopurinol (20 mgkg1d1, ), or a High Uric Acid Diet+Benzbromarone (20 mgkg1d1, ) for 10 Weeks
Each point represents the meanS.E. of 7 to 10 mice. Symbols show a signicant difference from apoE/ mice fed a normal diet+vehicle (*) or a high uric acid
diet+vehicle (#), *** p<0.001, ## p<0.01, ### p<0.001.

Fig. 4. Serum Concentrations of TC (A) and TG (B) in apoE/ Mice Fed a Normal Diet+Vehicle (), a High Uric Acid Diet+Vehicle (), a High
Uric Acid Diet+Allopurinol (20 mgkg1d1, ), or a High Uric Acid Diet+Benzbromarone (20 mgkg1d1, ) for 10 Weeks
Each point represents the meanS.E. of the values for 7 to 10 mice. Symbols show a signicant difference from apoE/ mice treated with a high uric acid diet+vehicle
(*), * p<0.05, *** p<0.001.

signicantly lower in the benzbromarone group than in the

high uric acid diet group (Fig. 5). Figure 6 shows photomicro-
graphs of atherosclerotic lesions in the aorta. Atherosclerotic
lesions were smaller in the hearts of mice in the allopurinol
and benzbromarone groups than in mice in the high uric acid
diet group. Total atherosclerotic lesion size was 73% and 58%
smaller in the allopurinol and benzbromarone groups than in
the high uric acid diet group at the end of the experiment (Fig.
7).

DISCUSSION

In this study, we examined the influence of uric acid, al-

lopurinol, and benzbromarone on arteriosclerosis. We cre-
ated hyperuricemic mice by feeding apoE/ mice a uric
acid-enriched diet. In many rodents, the serum uric acid level
is low because uric acid is further metabolized by uricase.
Therefore, there are few animal models for evaluating drugs
for hyperuricemia. In this study, the uric acid-enriched diet
contained 5% potassium oxonate, which is an inhibitor of uri-
case, and 2.5% uric acid, which was given to raise serum uric
Fig. 5. Oxidative Stress in apoE/ Mice Fed a Normal Diet+Vehicle,
a High Uric Acid Diet+Vehicle, a High Uric Acid Diet+Allopurinol
(20 mgkg1d1), or a High Uric Acid Diet+Benzbromarone
(20 mgkg1d1) for 10 Weeks
Each column represents the meanS.E. for 6 to 11 mice. Symbols show a signi-
cant difference from apoE/ mice fed a high uric acid diet+vehicle (*), ** p<0.01.
December 20141869
Fig. 6. Cross Sections of Aortic Sinus and Valve Cusps in apoE/ Mice Fed a Normal Diet+Vehicle (A), a High Uric Acid Diet+Vehicle (B), a High
Uric Acid Diet+Benzbromarone (20 mgkg1d1; C), or a High Uric Acid Diet+Allopurinol (20 mgkg1d1; D) for 10 Weeks
The arrow shows deposition of lipid.
Fig. 7. Arteriosclerotic Areas in apoE/ Mice Fed a Normal
Diet+Vehicle, a High Uric Acid Diet+Vehicle, a High Uric Acid
Diet+Allopurinol (20 mgkg1d1), or a High Uric Acid Diet+
Benzbromarone (20 mgkg1d1) for 10 Weeks
Each column represents the meanS.E. for 5 to 7 mice. Symbols show a signi-
cant difference from apoE/ mice fed a high uric acid diet+vehicle (*), * p<0.05,
** p<0.01.
acid levels. As a result, the serum concentration of uric acid
was signicantly higher in the high uric acid diet group than
in the normal diet group (about 2.5-fold) and serum uric acid
concentrations in the allopurinol, benzbromarone, and normal
groups were similar. This animal model is thus useful for
evaluating drugs for the treatment of hyperuricemia.
Total atherosclerotic lesion size did not signicantly differ
between the normal and high uric acid diet groups. However,
total lesion size was markedly smaller in the allopurinol and
benzbromarone groups than in the high uric acid diet group.
Plump et al. reported that at 10 weeks of age, apoE-decient
mice have high plasma cholesterol levels and have already
developed atherosclerotic lesions in the aorta and coronary
and pulmonary arteries.13) We are the rst to report that al-
lopurinol and benzbromarone control the progression of arte-
riosclerosis in apoE/ mice. Engberding et al. reported that
allopurinol represents a potential novel strategy for preventing
left ventricular remodeling and dysfunction after myocardial
infarction.14) There have been no such reports for benzbroma-
rone. It is interesting that in our study, allopurinol and benz-
bromarone inhibited atherosclerotic progression in an animal
model similar to human metabolic syndrome.
Serum TC and TG concentrations were signicantly lower
in the allopurinol group than in the high uric acid diet group.
At present, the mechanism behind this reduction is not clear,
and further in vitro and clinical studies are needed. Allopuri-
nol inhibits xanthine oxidase activity and suppresses uric acid
biosynthesis.15,16) Xanthine oxidase generates uric acid and
reactive oxygen species. Allopurinol, and its major active me-
tabolite oxypurinol, thus reduces reactive oxygen species by
inhibiting xanthine oxidase. Although the effect was not sig-
nicant, allopurinol reduced oxidative stress in our study. Re-
active oxygen species are characteristic of atherosclerosis,17,18)
and allopurinol may control the progress of atherosclerosis
by lipopenic action, decreasing the level of reactive oxygen
species. On the other hand, no decrease in serum lipid was
observed in the benzbromarone group, but there was a signi-
cant decrease in oxidative stress. Inokuchi et al. reported that
benzbromarone enhances adiponectin production by activating
peroxisome proliferator-activated receptor (PPAR) gamma.19)
Adiponectin is a protein hormone that mediates suppression of
metabolic derangements that may result in type 2 diabetes and
atherosclerosis.20,21) Yamauchi et al. reported that globular adi-
ponectin can protect against atherosclerosis in vivo.22) Benz-
bromarone might have controlled the progress of arteriosclero-
sis by decreasing oxidative stress and increasing adiponectin.
In conclusion, a single rise in the uric acid level did not
increase the risk of atherosclerosis. This might be because
1870
uric acid acts as a radical scavenger and inhibits oxidation;
however, allopurinol and benzbromarone administration pre-
vents the development of atherosclerosis in apoE/ mice fed
a uric acid-enriched diet. The anti-atherosclerotic effect is
partly a result of lower serum TC concentrations and lower
serum oxidative stress, but other mechanisms should be inves-
tigated. Clinical studies have shown association of high levels
of serum uric acid with poor coronary collateral circulation
in patients with stable coronary artery disease.23) Some re-
ports have suggested that allopurinol reduces cardiovascular
risks.2426) Higgins et al. reported that allopurinol reduces
central blood pressure and carotid intima-media thickness
progression at 1 year versus a placebo in patients with recent
ischemic stroke and transient ischemic attack.25) On the other
hand, Kok et al. reported that allopurinol therapy in patients
with gout does not yield benecial cardiovascular outcomes.27)
Okuda et al. reported that hyperuricemia may not contribute
to an increase in serum C-reactive protein (CRP), which is
associated with increased risk for myocardial infarction, ath-
erosclerosis, and peripheral artery diseases, but benzbroma-
rone may have a favorable effect on CRP.28) Further research
is needed to determine the possible utility of allopurinol and
benzbromarone in the treatment of cardiac disease.
Acknowledgments The authors are grateful to associate
professor Satomi Kagota and Ms. Kana Maruyama for their
suggestions and support. We also thank our colleagues for
their helpful advice and support.
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