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Pomegranate juice: a heart-healthy fruit juice
Arpita Basu and Kavitha Penugonda
Pomegranate juice is a polyphenol-rich fruit juice with high antioxidant capacity. In
limited studies in human and murine models, pomegranate juice has been shown
to exert significant antiatherogenic, antioxidant, antihypertensive, and
anti-inflammatory effects. Pomegranate juice significantly reduced atherosclerotic
lesion areas in immune-deficient mice and intima media thickness in cardiac
patients on medications. It also decreased lipid peroxidation in patients with type 2
diabetes, and systolic blood pressure and serum angiotensin converting enzyme
activity in hypertensive patients. Thus, the potential cardioprotective benefits of
pomegranate juice deserve further clinical investigation, and evidence to date
suggests it may be prudent to include this fruit juice in a heart-healthy diet.
© 2009 International Life Sciences Institute
INTRODUCTION
According to the findings of the National Vital Statistics
Report (2008) and the Morbidity and Mortality Weekly
Report (2007) of the Centers for Disease Control and
Prevention (CDC), cardiovascular disease (CVD) con-
tinues to rank high among the leading causes of mor-
bidity and mortality in adults in the United States.1,2
While diet and increased physical activity constitute the
primary preventive health approach, the role of plant-
based bioactive compounds or phytochemicals has
attracted much attention due to their unique cardio-
protective benefits.3–6 Several epidemiological studies
suggest that dietary patterns characterized by relatively
high intakes of fruits and vegetables are significantly
associated with reduced risks of coronary heart disease
(CHD) and stroke.7–9 Fruits and vegetables present a
heart-healthy and colorful array of phytochemicals
including carotenoids, and polyphenols like flavonoids,
resveratrol, and ellagitannins, isothiocyanates, and orga-
nosulfur compounds, each of which has been shown
to be associated with lower risks of cardiovascular
disease.10–16 However, observational studies and clinical
trials investigating the cardiovascular health benefits of
fruits and vegetables, attribute these effects to the com-
bination of phytochemicals, fiber, and other nutrients in
whole food intake, rather than the sole effects of an indi-
vidual component. Phytochemicals are potent anti-
oxidants and anti-inflammatory agents, thereby
counteracting oxidative damage and inflammation
which underlie the pathogenesis of CVD.17–20 Thus, in
addition to the general recommendation of consuming
five to nine servings of fruits and vegetables daily,21
emphasis is needed on the importance of the specific
phytochemical-containing fruits and vegetables that
have been shown to lower CVD risk factors in patients
and in healthy subjects.22–26 While the chemistry, bio-
availability, efficacy, and safety of novel phytochemicals
are being identified, it is prudent for nutrition research-
ers to emphasize their role in the prevention and treat-
ment of clinical outcomes at different stages of CVD,
and dissemination of this information to the general
public.
ATHEROSCLEROSIS, OXIDATIVE STRESS,
AND INFLAMMATION
Atherosclerosis, a major degenerative disease of arteries
involves a series of inflammatory and oxidative modifi-
cations within the arterial wall.27 Figure 1 exhibits the role
of oxidative stress and inflammation in the initiation and
progression of atherosclerosis, as postulated by previous
Affiliations: A Basu and K Penugonda are with the Department of Nutritional Sciences, 301 Human Environmental Sciences, Oklahoma
State University, Stillwater, Oklahoma, USA.
Correspondence: A Basu, Department of Nutritional Sciences, 301 Human Environmental Sciences, Oklahoma State University, Stillwater,
OK 74078-6141, USA. E-mail: arpita.basu@okstate.edu, Phone: +1-405-744-4437, Fax: +1-405-744-1357.
Key words: antioxidants, atherosclerosis, ellagic acid, hypertension, pomegranates
Emerging Science
doi:10.1111/j.1753-4887.2008.00133.x
Nutrition Reviews® Vol. 67(1):49–56 49
research.28–31 Emerging research shows that obesity,
hypertension, diabetes mellitus, dyslipidemia, smoking,
aging, diets rich in saturated fats, and reduced physical
activity are the established risk factors for
atherosclerosis,30,32–39 which is also characterized by
inflammation and oxidant burden.28,39
Oxidative stress, an imbalance between free radical
formation and antioxidant status,is the major contributor
to CVD, and inflammation is a manifestation of oxidative
stress. Oxidative stress induces inflammation by acting on
the pathways that generate inflammatory mediators like
adhesion molecules and pro-inflammatory cytokines.40,41
Recent human studies have shown significant positive
associations between oxidative stress and inflammation
and indicators of vascular damage, like impaired endo-
thelial function42 and arterial stiffness.29,31,43 Oxidative
stress and inflammation also induce vascular smooth
muscle cell (VSMC) activation and proliferation, angio-
genesis, lipid peroxidation, and platelet activation.33,44,45
C-reactive protein (CRP), vascular cell adhesion
molecule-1 (VCAM-1), tumor necrosis factor- a(TNF-
a), interleukin-1 (IL-1), interleukin-18 (IL-18), soluble
CD40 ligand (sCD40L), and monocyte matrix metallo-
proteinase 9 (MMP-9) are biomarkers of inflamma-
tion.46,47 Whereas, lipid peroxidation, oxidized-LDL, and
urinary 8-isoprostane levels are the oxidative biomarkers
of CVD risk factors.48
Oxidative stress and inflammation lead to endothe-
lial dysfunction by reducing nitric oxide (NO) bioavail-
ability due to the formation of peroxy nitrite, which is
cytotoxic.42,49,50 Inflamed endothelial cells (EC) express
VCAM-1 and promote monocyte adhesion, an initial
step in atherosclerosis. Selectins, integrins, and mono-
cyte chemoattractant protein-1 (MCP-1) expressed on
EC mediate attachment and migration of monocytes
into the intima, where they reside and multiply.
Inflamed intima expresses macrophage colony stimulat-
ing factor (M-CSF), which promote monocyte matura-
tion into macrophage. Atherogenic lipoproteins, like
low-density lipoproteins (LDL) and very-low-density
lipoprotein (VLDL), deposit in subintimal space and
undergo oxidative modifications resulting in the forma-
tion of oxidized LDL. Macrophages express scavenger
receptors and then engulf oxidized LDL to form lipid-
laden foam cells. Macrophages further progress the
process of atherosclerosis by secreting pro-inflammatory
cytokines like TNF-a,IL-1b. T cells join macrophages
and promote plaque formation by inducing VSMC
migration and proliferation. During the final stage,
VSMC express enzymes that degrade collagen, weaken
Figure 1 Oxidative stress and inflammation in initiation and progression of atherosclerosis.
(1) VCAM-1 promoting monocyte adhesion. (2) MCP-1 mediating monocyte migration into intima. (3) M-CSF promoting
monocyte maturation into macrophage. (4) LDL deposition in intima and oxidative modification to Ox-LDL. (5) Macrophages
engulfing Ox-LDL through SR and converting as foam cells. (6)T cells promoting VSMC proliferation and migration into intima.
(7) Plaque formation: foam cells surrounded by VSMC. Macrophages, T cells, foam cells, and VSMC secrete pro-inflammatory
cytokines and collagenases that aggravate the process of atherosclerosis and lead to thrombotic event.
Abbreviations: VCAM-1, vascular cell adhesiom molecule-1; MCP-1, monocyte chemoattractant protein-1; M-CSF, macrophage
colony-stimulating factor; VSMC, vascular smooth muscle cell; SR, scavenger receptor.
Nutrition Reviews® Vol. 67(1):49–5650
the fibrous plaque cap and make it prone to rupture.
Inflammatory stimuli also increase the expression of
pro-coagulant tissue factor, which triggers thrombus
formation when the plaque ruptures. Thrombus forma-
tion leads to acute coronary syndrome.27,46,47,51 Thus,
both oxidative stress and inflammation initiate, partici-
pate in, and enhance the process of atherosclerosis, and
are the principal targets of therapeutic interventions
with dietary phytochemicals, in preserving the endothe-
lium or reversing atherosclerosis.23,52–58
POMEGRANATE POLYPHENOLS
Antioxidant potency and bioavailability
Pomegranate fruit (Punica granatum L.) cultivated in
India, Spain, Israel, and the United States has been rated to
contain the highest antioxidant capacity in its juice,when
compared to other commonly consumed polyphenol-
rich beverages in the United States.59,60 The antioxidant
capacity of pomegranate juice was shown to be three
times higher than that of red wine and green tea, based on
the evaluation of the free-radical scavenging and iron-
reducing capacity of the juices.61 It was also shown to have
significantly higher levels of antioxidants in comparison
to commonly consumed fruit juices, such as grape, cran-
berry, grapefruit, or orange juice.62,63 The principal anti-
oxidant polyphenols in pomegranate juice include the
ellagitannins and anthocyanins.61 Ellagitannins account
for 92% of the antioxidant activity of pomegranate juice
and are concentrated in the peel, membranes, and piths of
the fruit. Punicalagins are the major ellagitannins in the
whole fruit and can be hydrolyzed to ellagic acid (EA) and
other smaller polyphenols in vivo.64 Commercial pome-
granate juice obtained by pressing the whole pomegran-
ate fruit and its peels contains significant amounts of the
water-soluble punicalagins, and these levels are variable
depending on the fruit cultivar, processing, and storage
conditions.61,65
The potential health benefits of pomegranate juice
consumption make it crucial to understand the bioavail-
ability of pomegranate polyphenols. An acute supple-
mentation of 800 mg of pomegranate extract containing
330 mg of punicalagins and 22 mg of EA (POMELLA,
Noblesville, IN) in 11 healthy volunteers, led to the detec-
tion of ellagitannin metabolites, including EA, uroli-
thin A, hydroxyl-urolithin A, urolithin B, urolithin
A-glucuronide, and dimethylellagic acid glucuronide
(DMEAG) in plasma samples drawn between 2 and 24 h
postprandial. High interindividual variability was
observed in the pharmacokinetics of these metabolites,
while no intact punicalagins were detected. The antioxi-
dant capacity of plasma was increased significantly by
32% at 0.5 h postprandial, while no effects were observed
on the generation of reactive oxygen species and biomar-
kers of inflammation.59
Consumption of 180 mL of pomegranate juice con-
taining 25 mg of EA (POM®Wonderful, Los Angeles, CA)
byahealthyhumansubjectledtothedetectionofEAat
a maximum concentration of 32 ng/mL in a 1 h post-
prandial plasma sample and was shown to be rapidly
eliminated by 4 h. No data were reported on other ellagi-
tannin metabolites.64 Data reported by the same study
group, following supplementation of 180 mL of pome-
granate juice concentrate (POM®Wonderful, Los Angeles,
CA) in 18 healthy volunteers, showed that EA was present
in all plasma samples at approximately 1 h post ingestion.
However, EA metabolites, mainly DMEAG and uroli-
thins, were also detected in plasma and urine of most
subjects; the authors suggest genetic polymorphisms in
EA-metabolizing enzymes account for these interindi-
vidual variabilities.66
On the other hand, pharmacokinetic data on
laboratory-prepared pomegranate juice polyphenols in
healthy volunteers or in patients with chronic obstructive
pulmonary disease in Europe showed undetectable levels
of punicalagins or EA in plasma or urine samples.67,68
Thus, on the basis of limited human studies, it
appears that estimation of the bioavailability of pome-
granate polyphenols is affected by several factors, includ-
ing: interindividual variability, differential processing of
pomegranate juice, as well as the use of analytical tech-
niques sensitive enough to detect low postprandial con-
centrations of these metabolites. Ellagic acid may be a
more stable biomarker in comparison to the intact puni-
calagins and other ellagitannin metabolites, which are
non-detectable and highly variable in human plasma and
urine, respectively.
Therapeutic effects in diabetes and atherosclerosis
A recently reported study on the supplementation of
pomegranate juice (PJ), pomegranate fruit liquid
extract (POMxl), pomegranate polyphenol powder
extract (POMxp), or pomegranate ground flowers extract
(POMf) in an atherosclerotic mouse model for 3 months
revealed a significant reduction in the atherosclerotic
lesion area compared to the water-treated group.54 Inter-
estingly, the largest decrease in lesion area (70%) was
observed in mice supplemented with POMf, which had
the highest content of total dietary fiber (30.2%) among
all fruit parts, and also led to a concomitant decrease in
serum glucose and cholesterol levels, compared to the
placebo group. PJ led to a significant reduction in the
atherosclerotic lesion area (44%), had no effects on serum
glucose and lipid levels, caused a significant decrease in
native LDL uptake by the peritoneal macrophages in
Nutrition Reviews® Vol. 67(1):49–56 51
mice, and stimulated HDL-mediated cholesterol efflux
from mice peritoneal macrophages, compared to the
placebo animals. All of the above pomegranate fruit
extracts and the juice were supplied by POM Wonderful
(Los Angeles, CA). While PJ had no fiber and a higher
polyphenol content (3600 mg/mL) compared to POMf
(166 mg/gm), the latter led to a larger decrease in lesion
area, which the authors attribute to the synergistic action
of polyphenols, dietary fiber, and other carbohydrates in
POMf. The researchers in this study further report sig-
nificant antioxidant capacities of all POM extracts,
though PJ had a higher free-radical-scavenging capacity
compared to POMf. Pomegranate seed oil, containing
only fatty acids and added antioxidants like tocopherols
and ascorbyl palmitate, was also used in the study, but
revealed no effects on atherosclerotic lesion size versus
placebo. The anti-atherogenic and vasculoprotective
activities of pomegranate fruit or extracts have also been
shown previously in mouse models;69–72 these can be
largely attributed to the unique blend of polyphenols and
complex carbohydrates, leading to cardiovascular health
benefits.
Inflammation
A 5-week supplementation of pomegranate juice or
pomegranate fruit extract (PFE) in obese Zucker rats fed
an atherogenic diet, showed a significant decrease in the
expression of vascular inflammation markers, thrombo-
spondin (TSP), and cytokine transforming growth
factor-b1(TGF-b1). Arterial endothelial-nitric oxide syn-
thase (eNOS) expressions were significantly increased in
animals supplemented with pomegranate juice or PFE, in
comparison to controls.55 Nitric oxide plays an important
role as an antioxidant and anti-inflammatory agent in the
endothelial cells and thereby attenuates the progression
of atherosclerosis.73 Pomegranate juice has also been
shown to prevent oxidative destruction of nitric oxide
and enhance its antioxidant and anti-inflammatory func-
tions.74 The anti-inflammatory effects of pomegranate
extracts have also been shown using a collagen-induced
arthritis mouse model,75 andtheyhavebeenshownto
reduce human prostate cancer xenografts in immune-
deficient mice by inhibiting inflammatory and angiogenic
pathways.76,77 However, these anti-inflammatory effects of
pomegranate juice in protecting the endothelium and
attenuating atherosclerosis have yet to be demonstrated
in clinical trials.
Safety
Supplementation of 710 mg or 1420 mg of an
ellagitannin-enriched pomegranate polyphenol extract
for 4 weeks was shown to be safe and well-tolerated in 64
overweight individuals with increased waist size and no
chronic disease. No treatment-related adverse events
were reported and hematology, chemistry, and urinalysis
laboratory reports were within the normal range.14 Oral
administration of a 6% punicalagin-containing diet for 37
days showed no toxic effects in Sprague-Dawley rats.78
Thus, on the basis of limited safety data, high doses of
pomegranate polyphenol extracts may be safe for human
health, though their safety in patients with cardiovascular
diseases has not been established.
POMEGRANATE JUICE CLINICAL TRIALS IN PATIENTS
WITH TYPE 2 DIABETES, ATHEROSCLEROSIS,
OR HYPERTENSION
An 8-week study was conducted among 22 type II dia-
betic patients supplemented with 40 g/day of concen-
trated pomegranate juice that contained significant
amounts of fiber (2.1 g/100 g), sugars (15.6 g/100 g), and
total polyphenols (875 mg/100 g).79 The study found a
significant reduction in total cholesterol and LDL-
cholesterol, while no effects were seen in triglycerides and
HDL-cholesterol concentrations. Prior to the start of the
study, the subjects were asked to participate in an 8-week
pre-study period, during which they carefully recorded all
dietary intakes and were trained in maintaining food
records. However, since this study had no control group,
it is difficult to interpret the findings.
In a 3-month study of 10 type II diabetic patients and
10 healthy controls consuming 50 ml of pomegranate
juice/day, no significant changes were noted in serum
glucose or lipid levels versus controls. However,the pome-
granate juice used in this study, containing significant
amounts of polyphenols (1979 mg/L of ellagitannins) but
no fiber, significantly decreased lipid peroxidation levels
and cellular uptake of ox-LDL by monocyte-derived
macrophages from the diabetic patients, which could
attenuate the progression of atherosclerosis.80
Pomegranate juice consumption (50 mL/day,
1979 mg/L ellagitannins) by ten patients with carotid
artery stenosis for 1 year led to a significant reduction in
mean intima-media thickness (IMT), systolic blood pres-
sure, and serum lipid peroxidation compared to baseline
values, while no changes were reported in serum glucose
and lipid levels. Five of ten patients continued to drink
pomegranate juice for up to 3 years but showed no addi-
tional benefits on IMT and systolic blood pressure,
although serum lipid peroxidation was further reduced
by 16% in these patients.Interestingly, these patients were
treated with hypercholesterolemic and anti-hypertensive
drugs throughout the study, indicating an additive or syn-
ergistic action of pomegranate juice on the clinical out-
comes.23 An earlier clinical trial also found reduced
systolic blood pressure and serum angiotensin converting
Nutrition Reviews® Vol. 67(1):49–5652
enzyme activity following 2 weeks of pomegranate juice
consumption (50 mL/day) in 10 hypertensive subjects,
adding further support to the anti-hypertensive effect of
pomegranate juice.81
The clinical studies discussed so far were conducted
in Middle Eastern countries; there have been limited
studies in Western populations on the anti-
atherosclerotic, anti-hypertensive, or anti-diabetic effects
of pomegranate juice. In a 3-month randomized, double-
blind, placebo-controlled study conducted in California
among 45 patients with incident myocardial ischemia,
pomegranate juice (240 mL/day, POM Wonderful, Los
Angeles, CA) caused a significant decrease in stress-
induced ischemia in comparison to placebo. No changes
were noted, however, in anthropometric measurements,
blood pressure, serum glucose, and lipid profiles versus
placebo.24 Thus, future clinical trials in patients on mul-
tiple medications will further strengthen the therapeutic
role of pomegranate juice in cardiovascular disease.
CONCLUSION
Pomegranate juice has shown significant anti-
atherosclerotic, anti-hypertensive, antioxidant, and anti-
inflammatory effects in human subjects and mouse
models (Figure 2). The principal mechanisms of action of
pomegranate juice may include the following: increased
serum antioxidant capacity, decreased plasma lipids and
lipid peroxidation, decreased oxidized-LDL uptake by
macrophages, decreased intima media thickness,
decreased atherosclerotic lesion areas, enhanced biologi-
cal actions of nitric oxide, decreased inflammation,
decreased angiotensin converting enzyme activity, and
decreased systolic blood pressure, thereby causing an
overall favorable effect on the progression of atheroscle-
rosis and the subsequent potential development of coro-
nary heart disease.
In comparison with commonly consumed fruit
juices, green tea,and black tea, which have been shown to
increase serum antioxidant capacity or decrease oxidative
damage of biomolecules,82–84 pomegranate juice exerts
additional cardioprotective benefits by decreasing or
reversing the progression of ischemic lesion areas, as well
as having a beneficial effect on intimal media thickness
and systolic blood pressure.Also, the fact that pomegran-
ate juice supplementation produced significant effects in
patients on multiple medications is promising because it
suggests pomegranate juice may be an effective source of
adjunct phytotherapy in patients at risk of heart disease
who are following a heart-healthy diet.
Thus, based on limited, but promising human data, it
appears that pomegranate juice supplementation in the
form of at least one to two cups a day may exert beneficial
Figure 2 Cardioprotective mechanisms of pomegranate polyphenols.
Abbreviations: PA, physical activity; EA, ellagic acid; ACE, angiotensin converting enzyme; NO, nitric oxide. inhibition by
pomegranate polyphenols.
Nutrition Reviews® Vol. 67(1):49–56 53
effects in subjects with type 2 diabetes and CVD, and
boost antioxidant defense mechanisms in healthy volun-
teers. Pomegranate polyphenol extracts, up to 1400 mg
appear to be safe, though most of the clinical trials that
have shown significant beneficial effects with pomegran-
ate juice have been made commercially or carefully
extracted under controlled laboratory settings by the
researchers. Pomegranate juice may be considered the
most heart-healthy fruit juice and awaits additional clini-
cal research to further strengthen support for its unique
cardioprotective effects.
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