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Lipid Research Laboratory, Technion Faculty of Medicine, The Rappaport Family Institute for Research in the Medical Sciences and Rambam Medical Center, Haifa, Israel
1To whom correspondence should be addressed.
 |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • ginger • LDL oxidation • atherosclerosis • E° mice
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and 1995
, Knekt et al. 1996
,
Muldoon and Kritchevsky 1996
). The polyphenolic flavonoids constitute a large class of related compounds consisting of two phenylbenzene (chromanol) rings linked through a pyran ring.
Different classes of flavonoids are present in different fruits,
vegetables and beverages such as tea and wine. Polyphenolic flavonoids
may prevent coronary artery disease by reducing platelet aggregation,
by reducing damage from ischemia and reperfusion, by reducing plasma
cholesterol levels or by inhibiting LDL oxidation (Aviram 1996
, Aviram and Fuhrman 1998a
, Belinky et al. 1998
, Demrow et al. 1995
, Formica and Regelson 1995
, Goker et al. 1995
;
Lanningham-Foster 1995
, Miura et al. 1995
, Sinatra and DeMarco 1995
,
Van Jaarsveld et al. 1996
, Xia et al. 1998
), a process which is thought to play a key role in the
pathogenesis of atherosclerosis (Aviram 1993c
and
1995
, Steinberg et al. 1989
,
Witztum and Steinberg 1991
). The antioxidant activity of
the flavonoids is related to their chemical structure
(Rice-Evans et al. 1996
, Van Acker et al. 1996
).
We and others have shown that dietary consumption of nutrients rich in
polyphenols, such as black or green tea (Serafini et al. 1994
), olive oil (Aviram and Kasem 1993
,
Visioli et al. 1995
), red wine (Frankel et al. 1993
, Fuhrman et al. 1995
, Hayek et al. 1997
, Kondo et al. 1994
, Maxwell et al. 1994
, Whitehead et al. 1995
) or the crude
extract of licorice, derived from the roots of the Asian plant
Glycyrrhiza glabra (Fuhrman et al. 1997a
),
protects LDL against lipid peroxidation and inhibits the development of
aortic atherosclerotic lesions.
Ginger (Zingiber Officinale Roscoe) is one of the world’s
best known spices, and it has also been universally used throughout
history for its health benefits. The dried extract of ginger contains
monoterpenes and sesquiterpenes. The main antioxidant active principles
in ginger are the gingerols and shogaols and some related phenolic
ketone derivatives (Fig. 1
). Ginger extract possesses antioxidative characteristics, since it can
scavenge superoxide anion and hydroxyl radicals (Cao et al. 1993
, Krishnakantha and Lokesh 1993
,
Reddy and Lokesh 1992
). Gingerol from ginger inhibited,
at high concentrations, ascorbate/ferrous complex induced lipid
peroxidation in rat liver microsomes (Reddy and Lokesh 1992
). Gingerol isolated from Zingiber was shown to inhibit
platelet function due to inhibition of thromboxane formation
(Guh et al. 1995
), and ginger was also suggested to
interfere with inflammation processes (Ozaki et al. 1991
). Furthermore, ginger acts as a hypolipidemic agent in
cholesterol-fed rabbits (Bhandari et al. 1998
,
Sharma et al. 1996
). Feeding rats ginger significantly
elevated the activity of hepatic cholesterol-7
-hydroxylase, the
rate-limiting enzyme in bile acids biosynthesis, thereby
stimulating cholesterol conversion to bile acids, resulting in
elimination of cholesterol from the body (Srinivasan and Sambaiah 1991
). In addition, a pure constituent from ginger
[E-8 beta, 17 epoxylabd-12-ene-15,16-dial (ZT)], was shown to inhibit
cholesterol biosynthesis in homogenated rat liver (Tanabe et al. 1993
).
|
, Maor et al. 1997
), and both of these
modified lipoproteins were shown to be present in the atherosclerotic
lesion of humans and E° mice (Aviram et al. 1995
) and
to be able to induce macrophage foam cell formation (Aviram
1993b
and 1993c
and 1995
,
Heinecke et al. 1991
, Suits et al. 1989
). |
MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Two stock solutions of the ginger extract at concentrations of 0.1 and 1 g/L were prepared in 22% alcohol and water (20 or 200 mg of ginger extract, respectively, were dissolved in 44 mL of ethanol, and the volume was then adjusted to 200 mL with water). Drinking solutions were prepared freshly every 3 d, by dilution of 25 mL of the respective ginger extract stock solution into 500 mL of water, resulting in final concentrations of 5 and 50 mg/L of ginger extract, respectively, in 1.1% alcohol and water.
Experimental design
The E° mice were kindly provided by Dr. Jan Breslow, the Rockefeller University, New York. At 6 wk of age, 60 E° mice were assigned randomly to three groups of 20. The mice received nonpurified diet, and in addition they consumed for 10 wk via their drinking water the following: group 1) placebo (control group), 1.1% alcohol and water (11 mL of alcohol in 1 L water); group 2) 25 µg of ginger extract/day in 1.1% alcohol and water; group 3) 250 µg of ginger extract/day in 1.1% alcohol and water.
The mice drank their water equally. Each mouse consumed ~5 mL of water/day and 4–5 g of food/day, and drinking ginger did not cause the mice to lose their appetite. The nonpurified diet was supplied by Koffolk Ltd. (Tel-Aviv, Israel)3 The body weight of mice before study entry (6 wk of age) was 20 ± 2 g, and at the end of the study at 16 wk of age was 25 ± 3 g. Consumption of ginger had no effect on body weight.
At the end of the experimental period, blood samples were collected from all mice for LDL separation. Within each experimental group of mice, blood samples were pooled from six to seven mice, thus obtaining three separate blood samples from each group.
Within each group, nine mice were injected intraperitoneally with 3 mL of thioglycolate (40 g/L) in saline, 4 d prior to killing, for isolation of mouse peritoneal macrophages (MPM). MPM were harvested prior to removal of the heart and aorta. MPM within each group were pooled from three mice, thus obtaining three separate samples from each group of mice. Then the mice were anesthetized with ethyl ether in a local nasal container. The heart and entire aorta were rapidly removed from all mice (n = 20) for histopathological analyses of aortic atherosclerotic lesions. The experimental protocol was approved by the Animal Care and Use Committee of the Technion, No. R/32/98.
Methods
Histopathology of aortic atherosclerotic lesion. The heart and entire aorta were rapidly removed and fixed by immersion in 3% glutaraldehyde in 0.1 mol/L sodium cacodylate buffer with 0.1 g/L calcium chloride, pH 7.4 at room temperature.
After ~1 h, under a binocular stereomicroscope, the aortic arch was dissected free from the surrounding fatty tissue, and the first 4 mm of the ascending aorta (beginning with the aortic valves) were removed and cut transversely with razor blades into four blocks of ~1 mm each.
Samples were kept in a fixative at room temperature overnight.
The samples were then rinsed and stored in 0.1 mol/L sodium cacodylate buffer containing 75 g/L sucrose prior to their treatment with 10 g/L aqueous solution of osmium tetroxide for 4 h. This procedure was followed by cacodylate rinse and dehydration in ascending ethanols, prior to propylene oxide and by embedding in epoxy resin ("Eponate 12"; Pelco Int., Redding, CA). The blocks were orientated so that transverse section of the aorta could be cut. After heat polymerization (18 h at 60°C), the blocks were trimmed and 1-µm sections, cut with diamond knives on an LKB "Nova" ultramicrotome (LKB, Bromma, Sweden). The sections were mounted on glass slides and stained with 1 g/L toluidine blue in 10 g/L borax (sodium tetraborate). In these toluidine blue-stained sections, the lipid deposits appear a green color and are easily visualized in the sections. When sufficient semi-thin sections were sampled from all blocks, the remainder of the blocks were cut into much thicker sections (150–200 µm) for macroscopic observation. The lesion lipid contents of these thicker sections were stained intensely black (from the prolonged osmium treatment), permitting lesion areas to be easily determined histomorphometrically. Only the area of the aortic arch was examined because this area is especially prone to atherosclerosis in apo E gene knockout mice.
Mouse peritoneal macrophages preparation. MPM were harvested from the peritoneal fluid of the E° mice 4 d after intraperitoneal injection into each mouse of 3 mL of thioglycolate (40 g/L) in saline. The cells (10–20 x 106/mouse) were washed and centrifuged three times with phosphate-buffered saline (PBS) at 1000 x g for 10 min and then resuspended to 109cells/L in Dulbecco Modified Eagle’s Medium (DMEM) (Biological Industries, Beth Haemek, Israel) containing 150 mL/L horse serum (heat-inactivated at 56°C for 30 min), 100,000 U/L penicillin, 100 mg/L streptomycin and 2 mmol/L glutamine. The cell suspension was dispensed into 35-mm plastic Petri dishes and incubated in a humidified incubator (5% CO2, 95% air) for2 h. The dishes were washed once with 5 mL DMEM to remove nonadherent cells, and the monolayer was then incubated under similar conditions for 18 h before the beginning of the experiment.
Cholesterol synthesis. Cellular cholesterol biosynthesis was assayed by incubation of the cells for 18 h with 3H-acetate (12.3 Bq/L), after which cellular lipids were extracted in hexane/isopropanol (3:2, v/v), separated by TLC on silica gel plates and developed in hexane/ether/acetic acid (80:20:1.5, v/v/v). Unesterified cholesterol spots were visualized by iodine vapor (using the appropriate standard) scraped into scintillation vials and counted in a ß-counter.
LDL preparation.
LDL were isolated from blood samples drawn from the E° mice before
and 10 wk after ginger administration, by discontinuous density
gradient ultracentrifugation (Aviram 1993a
) and dialyzed
against saline-Na EDTA (1 mmol/L). Before the oxidation study, LDL
were diluted in PBS to 100 mg of protein/L and dialyzed overnight
against PBS at 4°C to remove the EDTA. LDL protein concentration was
determined with the Folin phenol reagent (Lowry et al. 1951
).
Human LDL was prepared from human plasma derived from healthy donors.
LDL was radioiodinated by the iodine monochloride method as modified
for lipoproteins (Bilheimer et al. 1972
).
125I oxidized LDL (125I-Ox-LDL) was prepared by incubating 125I-LDL that was previously dialyzed against PBS, with 10 µmol/L of CuSO4 for 24 h at 37°C.
Macrophage-mediated oxidation of LDL. MPM (1 x 106/35 mm dish) were incubated for 18 h at 37°C in the incubator with human LDL (100 mg protein/L) in DMEM, that was supplemented with 2 µmol/L CuSO4. Oxidation was terminated by the addition of 1 mmol/L Na2 EDTA and refrigeration at 4°C. The extent of LDL oxidation was measured directly in the medium.
Macrophage uptake of 125I-oxidized LDL.
MPM were incubated for 5 h at 37°C with DMEM medium supplemented
with 100,000 U/L penicillin, 100 mg/L streptomycin and 2 mmol/L
glutamine, and 0.2% bovine serum albumin, in the presence of
125I-Ox-LDL (10 mg of protein/L). Macrophage degradation of
the labeled lipoprotein was measured in the collected medium as the
trichloroacetic acid-soluble noniodide radioactivity. Then the
cells were washed gently (3x) with cold PBS and dissolved in 0.1 mol/L
NaOH. Aliquots of 0.5 mL were taken for radioactivity counting in a
gamma counter for estimating cell-associated lipoprotein, and
aliquots of 0.1 mL were taken for protein determination (Lowry et al. 1951
).
LDL oxidation and aggregation.
Oxidation of LDL was carried out in a shaking water bath at 37°C
under air, in plastic tubes, 1 cm in diameter by incubating the LDL
with freshly prepared CuSO4 (5 µmol/L). Oxidation was
terminated by refrigeration at 4°C and addition of 0.1 mmol/L of
Na2 EDTA to chelate the copper ions. LDL oxidation was
determined immediately by measuring the formed amount of thiobarbituric
acid reactive substance (TBARS)(Buege and Aust 1978
).
Formation of conjugated dienes was continuously monitored by measuring
the increase in absorption at 234 nm (Esterbauer et al. 1989
). LDL-associated lipid peroxide formation was
determined with a cholesterol color reagent as previously described
(El-Saadani et al. 1981
).
LDL aggregation was induced by vigorous vortexing and was assessed by recording of the changes in optical density at 680 nm every 10 s.
Free radical scavenging capacity.
The free radical scavenging capacity of the ginger extract was analyzed
by the 1,1-diphenyl-2-picryl-hydrazyl assay (Blois 1958
).
Cholesterol and triglycerides levels were determined by commercially available kits.
Statistical analyses. The Student’s t test was used to analyze the significance of differences between control and the experiment groups. Each experimental group was separately compared to the control (placebo).
Results are given as means ± SD.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Aortic arch derived from all mice studied (control and those that consumed ginger extract) showed the presence of atherosclerotic lesions. However, the atherosclerotic lesion area was 44% (P < 0.01) smaller in mice that consumed 250 µg of ginger extract/day (45.1 ± 6.6 mm2) compared to the lesion area in control mice (79.9 ± 6.2 mm2). No differences in lesion are observed within each group between mice that were injected with thioglycolate for peritoneal macrophage separation and those mice that were not treated with thioglycolate.
Photomicrographs of typical aortic arch atherosclerotic lesions are
shown for E° mice that consumed the placebo (Fig. 2A
). These lesions were large and consisted of many
lipid-laden macrophage foam cells. In mice consuming 250 µg of
ginger extract/day, the lesions were significantly smaller and
contained only a few foam cells (Fig. 2B
).
|
). Similarly, significant (P < 0.01) 29, 53 and 33%
reductions were obtained in plasma total cholesterol,
LDL-cholesterol and VLDL cholesterol concentrations, respectively
(Table 1)
.
|
Significant (P < 0.01) 45 and 60% reductions in LDL
oxidation, as determined by the TBARS assay, and significant
(P < 0.01) 36 and 47% reductions in LDL oxidation, as
determined by the lipid peroxide test, were obtained when LDL were
incubated with MPM derived from mice that consumed 25 or 250 µg of
ginger extract/day, respectively, compared to controls given the
placebo (Table 2
). Incubation of macrophages, which were derived from E° mice that
consumed 25 or 250 µg/d of ginger extract, with
125I-Ox-LDL, resulted in 43 and 47% reductions
(P < 0.01) in 125I-Ox-LDL
cellular degradation, and in 47 and 47.5% reductions (P
< 0.01) in cell-association of
125I-Ox-LDL, respectively, compared to controls
(Table 2)
.
|
).
|
Consumption of 25 µg/d of ginger extract for a period of 10 wk did
not affect the basal level of LDL-associated lipid peroxides.
However, consumption of 250 µg of ginger extract/d for 10 wk resulted
in a 62% (P < 0.01) reduction in the basal level of
LDL-associated lipid peroxides (Fig. 3A
), in comparison to LDL isolated from the control mice. In
parallel, consumption of 25 and 250 µg/d ginger extract resulted in
23% (P < 0.01) and 33% (P < 0.01)
inhibition of LDL aggregation (induced by vortexing), respectively
(Fig. 3B
).
|
). Ginger extract also inhibited copper ion-induced
formation of TBARS (Fig. 4B
) and of lipid peroxides (Fig. 4C)
in a dose-dependent manner, with an IC50
(the concentration needed to inhibit LDL oxidation by 50%) of 5.0 and
5.4 mg/L, respectively (Fig. 4)
.
|
Ginger extract exhibited a direct ability to scavenge free radicals.
The addition of 40 mg of ginger extract/L to DPPH solution induced a
38% decrease in the optical density at 517 nm within 100 s. At a
higher dose of 100 mg of ginger extract/L, the optical absorbance of
DPPH at 517 nm was reduced after 100 s by 65% (Fig. 5
). Addition of vitamin E (25 µmol/L), which served as a positive
control, to the DPPH solution induced a rapid decrease in the optical
density at 517 nm up to 98%, which reached a plateau already within
50 s (Fig. 5)
.
|
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Atherosclerosis is a multi-factorial disease associated with
different risk factors. Hypercholesterolemia is a major risk factor for
atherosclerosis (Dominiczak 1998
, Sniderman et al. 1980
), and reduction in plasma cholesterol concentration by
drug therapy has reduced cardiovascular incidence (Gotto and
Grundy 1999
, Katerndahl and Lawler 1999
).
Consumption of natural nutrients, capable of reducing plasma
cholesterol, thus, should also reduce development of atherosclerosis.
Our study demonstrated that dietary consumption of ginger extract by
E0 mice significantly reduced the
development of aortic atherosclerotic lesions, along with an impressive
reduction in the levels of plasma and LDL cholesterol. Hypolipidemic
and antiatherosclerotic effects of ginger extract were also
demonstrated in cholesterol-fed rabbits (Bhandari et al. 1998
, Sharma et al. 1996
). The
hypocholesterolemic effect of ginger could have possibly resulted, at
least in part, from the inhibition of cellular cholesterol biosynthesis
observed after consumption of ginger extract. However, in vitro
supplementation of macrophages with ginger extract had no inhibitory
effect on cholesterol synthesis, suggesting that in vivo, following
consumption and digestion, cellular cholesterol synthesis was inhibited
by some ginger extract-derived metabolite or by a secondary
mediator. Cholesterol biosynthesis in peritoneal macrophages may
represent cholesterol synthesis in the liver, which has a major role in
determining lipoprotein level in plasma. Reduced cellular cholesterol
biosynthesis is associated with increased activity of the LDL receptor,
which in turn leads to enhanced removal of LDL from plasma, resulting
in reduced plasma cholesterol concentration (Ness et al. 1996
). These results are in agreement with previously reported
data, showing that plant foods possess cholesterol-suppressive
capacity (O’Brien and Reiser 1979
). We have previously
reported that the plant food-derived ingredients, ß-carotene and
lycopene, also act as hypocholesterolemic agents, secondary to their
inhibitory effect on cellular cholesterol biosynthesis
(Fuhrman et al. 1997b
).
The anti-atherogenicity of ginger extract could also be attributed
to its direct antioxidative effects on macrophages as well as on plasma
LDL. Arterial wall macrophages play a major role during early
atherogenesis. Oxidative stress induces macrophage responses such as
increased capacity to oxidize LDL, increased Ox-LDL cellular
uptake, as well as macrophage lipid peroxidation (Fuhrman et al. 1994
). These lipid-peroxidized cells were shown to oxidize
LDL even in the absence of transition metal ions (Fuhrman et al. 1994
, Fuhrman et al. 1997c
), and this process
depends on the oxidative state of the LDL and that of the macrophage
(Aviram and Fuhrman 1998b
). Ginger extract was shown in
this study to decrease macrophage oxidative responses, in vivo as well
as directly in vitro. Supplementation of J-774 A.1 macrophages in vitro
with ginger extract resulted in reduced capacity of the cells to
oxidize LDL and reduced cellular uptake of Ox-LDL. These effects
were retained in MPM isolated after ginger extract consumption. Ginger
extract consumption can result in accumulation of active ingredients
within the cells, as well as in the cell plasma membrane, thus
affecting cellular enzymes, and plasma membrane receptors. We have
indeed shown that ginger extract consumption reduces the cellular
uptake of oxidized LDL, possibly due to steric modification of plasma
lipoprotein receptors.
The LDL oxidation hypothesis of atherosclerosis development suggests
that inhibition of LDL oxidation should result in the attenuation of
the development of atherosclerotic lesions. We have demonstrated indeed
that the reduced development of atherosclerotic lesions in
E0 mice that consumed ginger extract was
associated with reduced LDL oxidative state. This may be related to the
fact that ginger extract can act as a free radical scavenger. Similar
reduction of atherosclerotic lesion development along with reduced LDL
oxidative state was previously demonstrated in E0
mice supplemented with red wine, or its major polyphenols, catechin or
quercetin (Hayek et al. 1997
), or licorice, or its major
polyphenol, glabridin (Fuhrman et al. 1997a
).
LDL oxidation can lead to an additional atherogenic modification of
lipoproteins, i.e., LDL aggregation (Maor et al. 1997
).
Aggregated LDL are taken up by macrophages at enhanced rate, leading to
cellular cholesterol accumulation and foam cell formation
(Aviram 1993b
, Heinecke et al. 1991
,
Suits et al. 1989
). Macrophages can also cause LDL
aggregation, independently of their oxidation, following the secretion
of proteoglycans from the cells under certain atherogenic conditions
(Maor and Aviram 1998
). The present study demonstrated
that the susceptibility of LDL to aggregation, like their propensity to
oxidation, was also by ginger extract consumption. This effect can be
attributed to reduction in LDL oxidative state, as well as to possible
changes in macrophage-released proteoglycans. Furthermore, it is
also possible that ingredients of the ginger extract, such as
polyphenols, bind to LDL and interfere with the interaction between the
lipoprotein hydrophobic domains, which are involved in lipoprotein
aggregation induced by vortexing. The above results are in agreement
with our previous study, which demonstrated a reduced susceptibility of
LDL to aggregation in E0 mice following dietary
supplementation with red wine, or its major polyphenols, catechin or
quercetin (Hayek et al. 1997
).
We conclude that consumption of ginger extract may be proven beneficial in attenuation of atherosclerosis development, since it is associated with reduced macrophage-mediated oxidation of LDL, reduced uptake of oxidized LDL by macrophages, reduced oxidative state of LDL and reduced LDL aggregation. All these effects lead to a reduced cellular cholesterol accumulation and foam cell formation, the hallmark of early atherosclerosis.
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FOOTNOTES |
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3 Its ingredients are the following: 210 g/kg
total protein, 40 g/kg total fat, 45 g/kg cellulose, 70 g/kg ash, 8–12
g/kg calcium, 7–9 g/kg phosphor, 3 g/kg chlorides and 2.5 g/kg
natrium.
Manuscript received August 23, 1999. Initial review completed September 27, 1999. Revision accepted January 6, 2000.
|
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|---|
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