Potency of Watermelon (Citrullus lanatus) as Prevention and Maintenance

of Coronary Heart Disease

ABSTRACT
Background: Coronary heart disease (CHD) is the leading cause of death in the world and in
Indonesia. Maintenance of CHD nowadays by aspirin or statin has long term safety issues,
while healthy lifestyle is hard to be applied. In the other hand, society interest towards herbal
medicine has been increased. Therefore, we have to explore more Indonesian herbal as safe
medicine for CHD. Methods: Literature review from journals in the last 10 years. Keywords
used were “watermelon, lycopene, citrulline, CHD” on database pubmed, googlescholar,
highwire. Discussion: Watermelon (Citrullus lanatus) can prevent CHD due to lycopene and
citrulline. Prevention mechanism done by acting as antioxidant and anti-inflammation,
decrease cholesterol, atherosclerotic lesion, and blood pressure, also promoting endothelial
function. The effects of watermelon are higher than other similar fruits such as tomato,
papaya, and pink guava. Benefits of watermelon are easy to be found in most parts of
Indonesia, easy to be cultivated, cheap, tasty, and easy to be processed into various culinary
products. Side effect of watermelon could be avoided by not eating too much in the same
time. Conclusion: Watermelon has potency as prevention and maintenance of CHD, further
studies are called to explore the molecular mechanisms.

Keywords: watermelon, CHD, lycopene, citrulline

INTRODUCTION altering lifestyle is not as easy as it seems.

Coronary heart disease (CHD) is a disease
in which a waxy substance called plaque
builds up inside coronary arteries.
According to WHO, an estimated of 7.4
million deaths were due to CHD in 2012,
placed CHD as the leading cause of deaths
in the world including in Indonesia.1 This
high prevalence shows that CHD is one
great concern of health issue.
There are two types of CHD risk factors,
the modifiable and unmodifiable one.
Unmodifiable factors are gender and
family history, while modifiable factors
are high LDL cholesterol, low HDL
cholesterol, high blood pressure, obesity,
diabetes, depression, less physical
exercise, and smoking.2
One of the best prevention and treatment
of CHD is healthy lifestyle such as stop
smoking, cholesterol diet, and being
physically active. However, this will be
very challenging for most people because
Usage of medicine such as aspirin or statin
may help, but unfortunately long term use
of aspirin found to cause early-age
macular degeneration3, while statin may
increase risk of cognitive dysfunction and
diabetes in 10 year.4 Therefore, a safer
preventive and therapeutic strategy is
necessary for patient’s safety and
convenience.
In the other hand, there has been increased
awareness of society toward herbal
medicine, because herbal medicine
considered safer in long term use. There
are some plants which have been known to
help patient with CHD such as curcumin
(Curcuma longa), garlic (Allium sativum),
and mengkudu (Morinda citrofilia).5
Unfortunately not all people like the taste
of those herbal. Scientists also predict
there are still a lot more plants which have
impact toward cardiovascular disease but
still not known yet by the society.

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One of the recent finding in cardiovascular antioxidant and vasodilatory roles in
disease is watermelon. Watermelon has the human. Citrulline content in watermelon
capacity as anti-hypertension, anti- rind was higher than in watermelon flesh,
hyperlipidemia, anti-oxidant, anti- ie 3.34 to 2.33 g /kg.9 Besides the presence
inflammation, and promote endothelial of antioxidants, watermelon is also the
function.6,7 Watermelon is one of the fruit source of B vitamins (B1 and B6), as well
which is liked by many people, proven by as minerals such as potassium and
the high selling. Watermelon also could be magnesium.10
found easily in almost every parts of
Indonesia and not hard to be cultivated. 7
Those make watermelon to be affordable
in term of price and availability. Therefore,
it would be such a worthwhile contribution
to write about watermelon and its potency
as prevention and maintenance of coronary
heart disease.

MATERIALS AND METHODS

Writing methodology used was literature

review. The source of literatures consisted
of relevant journals with preference
materials published in the last 10 years.
The collected information noted, analyzed
for validity and reliability, interpreted and
compiled into one scientific literature
review. The keywords used for searching
literature were “watermelon, lycopene,
citrulline, CHD” on database pubmed,
googlescholar, and highwire. From 29
Figure 1. Botanical Classification of
journals that were reviewed, 18 were
Watermelon10
found to be suitable as references.

RESULT AND DISCUSSION Table 1. Comparison of lycopene in

several fruits11
Watermelon

Watermelon (Citrullus lanatus) is a fruit

which cultivates abundantly in tropical
regions8 like Indonesia. Watermelon is
very rich in lycopene, 1.5 times higher
than tomato. Lycopene is a carotenoid with
high antioxidant capacity and its content in
watermelon flesh ranging between 11.6-
14.3 mg/kg.9 Watermelon is also a rich
source of citrulline that has potential

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 Pathogenesis of Coronary Heart Disease
(CHD)

Coronary heart disease occurs when

plaque builds up inside the coronary
arteries. Plaque can harden and narrow the
arteries, reducing blood flow to heart
muscle. If the plaque rupture, a blood clot
can form on its surface and completely
block the flow of oxygen-rich blood to the
part of the muscle that fed by the artery.
When this occur, patient may feel like
pressure or squeezing in chest and also in
shoulders, arms, neck, jaw, or back. Over
time, CHD can weaken the heart muscle
and lead to heart failure and arrhythmias. 12
Detailed explanation about CHD
pathogenesis can be seen in figure 2.

Figure 2. Pathogenesis of Coronary Heart Disease and Watermelon Site of Action. Circled in
red; A: reducing blood cholesterol, B: prevent endothelial dysfunction, C: prevents oxidation of
LDL through antioxidant activity, D: reducing inflammatory response

Potency of Watermelon to Prevent in coronary heart disease are by decreasing

Coronary Heart Disease
Watermelon can prevent and maintain
condition of CHD patient, thus decreasing
its mortality because of lycopene and
citrulline. Role of lycopene and citrulline
blood pressure, promote endothelial
function, decrease blood cholesterol, and
anti-inflammation effect as described in
figure 3 and will be discussed further in
this review.

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 Figure 3. Mechanism of watermelon as prevention and maintenance of CHD

15mg/day lycopene supplementation

Antioxidant Effect
Lycopene found in watermelon is one of
the most powerful antioxidant among
major carotenoids. A study by Kim et al.
has shown lycopene could alleviate
oxidative stress commonly found in CHD
patient. After 8 weeks, subjects given
shows significant decrease of lymphocyte
DNA damage (-16.5 ± 3.43 μm, P=0.042)
and increased superoxide dismutase (SOD)
activity (2.37 ± 0.63 units/mL, P=0.014)
when compared to subjects given 6mg/day
supplementation and placebo groups as
shown in figure 4.12

Figure 4. Effects of 8 week lycopene supplementation in decreasing lymphocyte DNA

damage (left) and increasing SOD activity (right).1

4
Anti-inflammatory Effects

The core pathogenesis of CHD is inflammatory response from endothelial dysfunction.

Lycopene in watermelon can reduce inflammation by protect mtDNA against oxidative
damage13, also reduced the expression of inflammatory factors TGF-β1, collagen I, collagen
III, TNF-α, IL-1β, caspase-3, -8 and -9 and inhibit activation of NF-κB signaling pathway.14

In vivo assessment shows that Citrullus lanatus seed oil (CLSO) reduces volume of edema in
carrageenan-induced paw edema Wistar rats by 44.44% and 55.56% for 50 mg and 100 mg
supplementation, following 3 hours of supplementation as shown in table 2. In vitro study
also shown potent anti-inflammatory effects of CLSO using human red blood cell membrane
stabilization (HRBC) method, with 500 ug/mL CLSO extract exhibiting 78.50% RBC
protection as shown in Table 3. These results were comparable to the standard NSAID
diclofenac.15

Figure 5. Impact of Lycopene in Decreasing Inflammatory Factors Compared to Saline

Control

Table 2. Effects of Citrullus lanatus seed oil supplementation (shown in red box) in
decreasing carrageenan-induced paw edema volume in rats, compared to standard NSAID
diclofenac (shown in blue box).10

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 Table 3. In vitro effect of CLSO supplementation (shown in red box) compared to NSAID
diclofenac (shown in blue box), assessed using HRBC method.10

Endothelial Function, Blood Pressure, and Atherosclerotic Lesions

Watermelon supplementation has shown capability in improving endothelial function. This is

due to the fact that lycopene can protect cardiomyocytes from Endoplasmic reticulum (ER)-
stress-induced-apoptosis as seen in figure 6, as evidenced by reducing GRP78 mRNA
expression, the ratio of Bax/Bcl-2, caspase-12 and caspase-3 activity.16

For blood pressure, citrulline and arginine in watermelon has important role in urea formation
from ammonia and CO2 so urine production will be increased or known as diuretic. Diuretic
helps kidney eliminate salt and water which will decrease volume of fluid in the body so
cardiac output and

blood pressure will decrease. L-citruline from watermelon also will converted into L-
arginine, the substrate for nitric oxide (NO) production – a main regulator of arterial blood
pressure by vasodilatory effects. Clinical effects of watermelon in decreasing blood pressure
can be seen in Table 4 and Table 5.17

For atherosclerotic lesions, lycopene in watermelons shown ameliorative effects to those

lesions. In a study by Hu et al., subject groups given a high-fat diet and high dose lycopene
treatment develops far smaller lesions (5% coverage of the aortic surface) when compared to
groups given only high-fat diet as shown in Figure 7. This effect is similar to that of
fluvastatin, a standard drug for treating atheroscle.18

6
Figure 6. Clinical Effects of 5μM lycopene after 4h prior to 4h hypoxia exposure in neonatal
mouse cardiomyocites. (Lyc, Lycopene. H/R, hypoxia/reoxygenation)

Table 4. Hemodynamic parameters before and after watermelon supplementation Note

significant changes in brachial pulse pressure (bPP), arterial systolic BP (aSBP), arterial
pulse pressure (aPP), aortic augmentation index (Aix), and second systolic peak (P2), shown
inside red box.13

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 Table 5. Hemodynamic parameters before and after watermelon supplementation. MAP:
mean arterial pressure; ABI: ankle-brachial index. 11

Figure 7. Effects of lycopene supplementation on the size of aortic lesion (5%, shown in red
box) when compared to high-fat diet only group (48%, shown in yellow box) and fluvastatin
(5%,shown in blue box).18 P<0.05

Cholesterol Metabolism

Hypercholesterolemia has been a deciding risk factor in CHD development. Lycopene in

Citrullus lanatus has been shown to exhibit significant cholesterol-lowering effects that is
comparable to fluvastatin, a standard cholesterol-lowering drug. In the same study by Hu et
al. noted above, after 8 weeks the total cholesterol levels in the serum of the low and high
dose lycopene treated dose is 72% and 73% less than that of the high fat diet only group,
respectively. This effect is almost as potent as fluvastatin, which shows 76% decreased total
cholesterol levels as shown in figure 8.

8
 The same effects are also seen in triglyceride and low density lipoprotein (LDL) cholesterols.
Although there is also an increase in HDL levels, it is only significant in the fluvastatin-
treated group. In addition, after 8 weeks the level of oxidized LDL (ox-LDL) has shown to be
decreasing in lycopene treated groups, as well as an increase of interleukin-1 (IL-1) and
serum NO (P<0.05) as shown in table 6.18

Mechanism suspected in decreasing cholesterol synthesis is the role of lycopene which

reduce 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and expression,
modulation of low- density lipoprotein (LDL) receptor and acyl-coenzyme A:cholesterol
acyltransferase activity .19

Figure 8. Effects of lycopene supplementation (shown in red box) compared to fluvastatin

(shown in blue box) on total cholesterol (top-left), triglyceride (top-right), LDL cholesterol
(bottom-left), and HDL cholesterol (bottom-right).6

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Table 6. Effects of lycopene treatment on serum ox-LDL, NO, and IL-1 9P<0.05). C: control
group; F: high fat diet. FL1: HFD and low dose lycopene; FL2: HFD and high dose lycopene;
FF: HFD and fluvastatin.12
Weakness of Watermelon
In right dose, watermelon found to be safe
in long term use. But, when eaten too
much in the same time, lycopene in
watermelon may cause gastrointestinal
disturbance such as diarrhea, constipation,
bloating, and nausea to vomiting.
Potassium in watermelon also may cause
hyperkalemia. Fortunately, this effect
could be avoided by not eating too much
watermelon in the same time, so let the
body process lycopene and potassium
before taking more watermelon.7
CONCLUSION
Watermelon has potency to prevent and
maintain CHD due to lycopene and
citrulline with antioxidant and anti-
inflammatory effect, decrease cholesterol
metabolism, atherosclerotic lesion and
blood pressure, also promoting endothelial
function. Citrullus lanatus therapeutic
effect resembling synthetic drugs with
lower side effect therefore it could be used
as alternative prevention and maintenance
of CHD to decrease its mortality. There are
still high opportunity in further studies of
Citrullus lanatus molecular mechanism in
CHD.
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