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Effect of garlic on inflammation processes and atherosclerosis under human-like
conditions in APOE*3-Leiden mice
Sonia M.S. Espirito Santo
TNO Prevention and HealthGaubius Laboratory
The Netherlands
Leiden University Medical CenterDepartment of CardiologyThe Netherlands
• Development of high quality garlic under standardized conditions.
• Develop of a chemically well-characterized garlic material.
• Define organo-sulfur compounds metabolic pathway in the clove and in vivo after ingestion.
• Study in vitro and in vivo the influence of this standardized and well-characterized garlic material on atherosclerosis and cancer for disease prevention.
European Comunity Garlic and Health project
• Garlic has an historical record for its use in medicine.
• Some studies have suggested that garlic significantly reduces plasma lipid levels, systolic and diastolic blood pressure and that shows a strong antibiotic activity.Kik C, Kahane R, Gebhardt R. Nutr Metab Cardiovasc Dis. 2001;11:57-65.
• Garlic clinical trials and animal studies with well-characterized and standardized garlic material, with a consistent study design and dosage are poorly found in the last 15 years.
Garlic and health
Possible effects of garlic on lipid metabolism
CHOLESTEROL
SYNTHESIS
CONVERSION
CHOLESTEROL
UPTAKE
receptors
STORAGE
ESTERS
DIETARY
BILE ACIDS
LDL receptor
CHOLESTERYL
BILE
other
BILIARYCHOLESTEROL
SECRETION
LIVER
INTESTINE
CM
CM Remnants
VLDL
LDL
Possible effects of garlic on atherosclerosis
Lipid core
Media
Intima
Endothelium
LDL
O2
oxLDL
Thrombus
Collagen- degrading proteinases
Shear stress
Fibrous capMonocytes
Inflammation
Oxidation
Contradictory effects Contradictory effects attributedattributed to garlic to garlic
• Old human trials on healthy patients treated with garlic oil reported a decrease in plasma lipid levels.Bordia A, et al. Atherosclerosis.1975;21:15-19. Bordia A, et al.
• Recent human trials on hypercholesterolemic patients showed no effects of garlic powder (Kwai) and garlic oil treatment on plasma lipid levels.Simmons LA, et al. Atherosclerosis.1994;113:219-225. Berthold, et al. JAMA. 1998;279:1900-02. McCrindle BW, et al. Arch Pediatr Adolesc Med. 1998;152:1089-94. Isaacsohn JL, et al. Arch Intern Med.1998;158:1189-94. Gardner CD, et al. Atherosclerosis. 2001;154:213-220. Ziaei S, et al. Eur J Obstetrics & Gynecology. 2001;99:201-6.
• Allicin showed no effects on plasma lipid levels and decreased aortic fatty streaks-like lesions in hypercholesterolemic C57Black/6 mice. D. Abramovitz et al., Coronary Artery Disease, 1999, 10: 515-519.
• Induced-atherosclerosis in rabbits fed garlic oil and aged garlic extract (Kyolic) showed a decrease of aortic fatty streaks lesions.Bordia A, et al. 1980:428-37. Mand JK, et al. Indian Heart J. 1985;37:183-88. Efendy JL, et al. Atherosclerosis. 1997:132:37-42. Campbell JH, et al. J Nutr. 2001;131:1006S-09S. Durak I, et al. Nutr Metab Cardiovasc Dis. 2002 ;12:141-7.
• Hypercholesterolemic pigs and rats fed garlic oil and garlic powder (Kwai) showed no effects on atherosclerosis development.Heinle H,et al. Drug Res. 1994;44:614-17. Lee WM, et al. Exper Mol Pathol. 1980:33:345-8.
• Lipid metabolism
- No effects of garlic powders and isolated compounds on plasma lipid levels and markers of cholesterol synthesis and absorption under hyperlipidemic conditions.
- Morado 200 garlic powder showed an improved liver function, decreased plasma cholesterol levels and serum amyloid A levels under atherogenic conditions.
• Fast atherosclerosis development– No decreasing effect of garlic on atherosclerosis of the aortic
root was observed for all treatments.Espirito Santo SMS, et al. Effect of garlic powders and garlic isolated compounds on lipid metabolism. 2002.
Previous reported effects of garlic (LI111, Previous reported effects of garlic (LI111, Morado 200, Allicin and DADS) in APOE*3-Morado 200, Allicin and DADS) in APOE*3-
Leiden miceLeiden mice
Study the effect of 2 different doses of Printanor garlic powder
• under mild human-like conditions
• on inflammation related parameters
• on atherosclerosis development
by means of a hyperlipidemic and atherosclerosis-susceptible APOE*3-Leiden transgenic mice.
Effect of garlic on inflammation processes and atherosclerosis under
human-like conditions: Aim
• Printanor FR 2001 (0.5% Prin): 0.5% of dry garlic powder with low sulphur content.
• Printanor FR 2001 (5% Prin): 5% of dry garlic powder with high sulphur content.
• Kyolic (positive control): 0.16% of dry garlic powder rich in S-allylcysteine reported to result in 64% reduction of fatty streaks in New Zealand white rabbits. Campbell JH, Efendy JL, et al. J.Nutrition. 2001;131:1006S-1009S.
Effect of garlic on inflammation and atherosclerosis under human-like
conditions: Garlic powders
16 female APOE*3-Leiden mice per group
0.2% cholesterol diet for 28 weeks
• General parameters: Body weight, food intake, marker of liver function, plasma lipid levels, blood pressure, and fecal fatty acids.
• Inflammation related parameters: All body and vessel wall inflammation markers (Serum amyloid A, soluble ICAM, and von willebrand factor) and whole blood stimulation assay.
• Atherosclerosis related parameters: Aortic root lesions typing, and total lesion area.
Effect of garlic on inflammation and atherosclerosis under human-like conditions:
Experimental design
*
Control0.5%Prin
ControlKyolic
Control5% Prin
Effect of garlic on body weight gain of APOE*3-Leiden mice
Weeks
Bo
dy
wei
gh
t g
ain
(g
)
P<0.01
02468
10
0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 28
**
**
Effect of garlic on food intake and body temperature of APOE*3-Leiden mice
Food intake(g/mouse/day)
2.79 ± 0.08
2.87 ± 0.12
2.75 ± 0.16
2.88 ± 0.10
Control
0.5% Prin
5% Prin
Kyolic
Free fatty acids(mM)
0.73 ± 0.13
0.79 ± 0.11
0.60 ± 0.10
0.62 ± 0.18
*
*
Effect of garlic on fecal fatty acids excretion of APOE*3-Leiden mice
To
tal
fat
excr
etio
n
(µm
ol/
100g
mo
use
/day
)0
200
400
600
800
Control 0.5%Prin
5% Prin
Kyolic
*
P<0.05
0
1
2
3
4
5
To
tal
dry
fec
es
(g/
day
)
Control 0.5%Prin
5% Prin
Kyolic
*
Effect of garlic on liver function of APOE*3-Leiden mice
Pla
sma
AL
AT
lev
els
(U/L
)
Weeks
Control0.5%Prin
ControlKyolic
Control5% Prin
0
50
100
150
200
0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 28
Effect of garlic on plasma cholesterol levels of APOE*3-Leiden mice
Weeks
Ch
ole
ster
ol
leve
ls (
mM
) Control0.5%Prin
ControlKyolic
Control5% Prin
0
5
10
15
20
0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 28
Effect of garlic on plasma triglyceride levels of APOE*3-Leiden mice
Weeks
Tri
gly
ceri
des
lev
els
(mM
) Control0.5%Prin
ControlKyolic
Control5% Prin
0
1
2
3
4
0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 28
Effect of garlic on lipoprotein profile of APOE*3-Leiden mice
Cholesterol Triglycerides
Fractions
0
1
2
0 8 16 24 0 8 16 24 0 8 16 24 0 8 16 24
Control 0.5% Prin 5% Prin Kyolic
Before treatment with garlic preparations
0
1
2
0 8 16 24 0 8 16 24 0 8 16 24 0 8 16 24
mM
After treatment with garlic preparations
Effect of garlic on blood pressure of APOE*3-Leiden mice
Blo
od
pre
ssu
re
(mm
Hg
)
0
40
80
120
160
Control 0.5%Prin
5% Prin
Kyolic
12 weeks 16 weeks
Control 0.5%Prin
5% Prin
Kyolic
Effect of garlic on serum SAA and ICAM levels of APOE*3-Leiden mice
0
5
10
15
20
0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 28
Control0.5%Prin
Control5% Prin
ControlKyolic
SA
A (
µg
/ml)
ICA
M (
µg
/ml)
0
10
20
30
40
0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 28
Effect of garlic on plasma vWF levels of APOE*3-Leiden mice
050
100150200250
0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 28
vWF
(%
PP
rat
)
Control0.5%Prin
Control5% Prin
ControlKyolic
Effect of garlic on atherosclerosis development of APOE*3-Leiden mice
Lesion typing Lesion areaCholesterol exposure
0
100
200
300
400
500
0
20
40
60
80
100
Control 0.5%Prin
5% Prin
Kyolic Control 0.5%Prin
5% Prin
KyolicControl 0.5%Prin
5% Prin
Kyolicµ
m2 10
00
%mM
Type I-IIIType IV-V
0
50
100
150
200
250
Ch
ole
ster
ol
exp
osu
re
(mM
) R= 0.8136
Area (µm2 1000)
Correlation between cholesterol exposure and atherosclerosis lesion area after garlic
treatment of APOE*3-Leiden mice
Y= 0.8308x + 289.82
0
200
400
600
0 50 100 150 200
Dietary garlic treatment on APOE*3-Leiden mice results in:
• Decreased body weight gain (P=0.007) for the 5% Printanor treated group:
– lower (P=0.032) plasma free fatty acids
– higher (P=0.043) fecal fatty acids excretion
• No effects on liver function, plasma lipids and glucose levels, and on blood pressure.
• No effects on markers of all body and vessel wall inflammation and on atherosclerosis development.
Conclusions
Human intervention study
Collaboration with CHDR-Leiden
Future perspectives
Ackowledgements
Sonia Espirito Santo
Erik OffermanRia van den Hoogen
Louis Havekes
Bart van VlijmenHans Princen
Wim van Duyvenvoorde