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Sonia M.S. Espirito Santo

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 Health Gaubius Laboratory The Netherlands. Leiden University Medical Center Department of Cardiology The Netherlands.

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Sonia M.S. Espirito Santo

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  1. 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 Health Gaubius Laboratory The Netherlands Leiden University Medical Center Department of Cardiology The Netherlands

  2. European Comunity Garlic and Health project • 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.

  3. Garlic and health • 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.

  4. Possible effects of garlic on lipid metabolism CM Remnants CM LDL LIVER LDL receptor UPTAKE SYNTHESIS other receptors CHOLESTEROL STORAGE CHOLESTERYL ESTERS VLDL CONVERSION SECRETION BILE ACIDS BILIARY CHOLESTEROL BILE INTESTINE DIETARY CHOLESTEROL

  5. Possible effects of garlic on atherosclerosis Shear stress Inflammation Oxidation Intima Fibrous cap Media Monocytes LDL Thrombus Endothelium oxLDL O2 Lipid core Collagen- degrading proteinases

  6. Contradictory effects attributed 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.

  7. Previous reported effects of garlic (LI111, Morado 200, Allicin and DADS) in APOE*3-Leiden mice • 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.

  8. Effect of garlic on inflammation processes and atherosclerosis under human-like conditions: Aim 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.

  9. Effect of garlic on inflammation and atherosclerosis under human-like conditions: Garlic powders • 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.

  10. Effect of garlic on inflammation and atherosclerosis under human-like conditions: Experimental design 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.

  11. Effect of garlic on body weight gain of APOE*3-Leiden mice Control Control Control Kyolic 0.5%Prin 5% Prin 10 8 Body weight gain (g) 6 * 4 * * * 2 * 0 0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 28 Weeks P<0.01

  12. Effect of garlic on food intake and body temperature of APOE*3-Leiden mice Control 0.5% Prin 5% Prin Kyolic Food intake (g/mouse/day) 2.79 ± 0.08 2.87 ± 0.12 2.75 ± 0.16 2.88 ± 0.10 Free fatty acids ( mM) 0.73 ± 0.13 0.79 ± 0.11 * 0.60 ± 0.10 * 0.62 ± 0.18

  13. Effect of garlic on fecal fatty acids excretion of APOE*3-Leiden mice 800 5 * * 4 600 3 Total dry feces (g/ day) Total fat excretion (µmol/100g mouse/day) 400 2 200 1 0 0 Control 0.5% Prin 5% Prin Kyolic Control 0.5% Prin 5% Prin Kyolic P<0.05

  14. Effect of garlic on liver function of APOE*3-Leiden mice Control Control Control Kyolic 0.5%Prin 5% Prin 200 150 Plasma ALAT levels (U/L) 100 50 0 0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 28 Weeks

  15. Effect of garlic on plasma cholesterol levels of APOE*3-Leiden mice Control Control Control Kyolic 0.5%Prin 5% Prin 20 15 Cholesterol levels (mM) 10 5 0 0 4 8 12 16 20 24 0 4 8 12 16 20 24 28 0 4 8 12 16 20 24 Weeks

  16. Effect of garlic on plasma triglyceride levels of APOE*3-Leiden mice Control Control Control Kyolic 0.5%Prin 5% Prin 4 3 Triglycerides levels (mM) 2 1 0 0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 28 Weeks

  17. Before treatment with garlic preparations 2 Control 0.5% Prin 5% Prin Kyolic 1 0 0 8 16 24 0 8 16 24 0 8 16 24 0 8 16 24 mM After treatment with garlic preparations 2 1 0 0 8 16 24 0 8 16 24 0 8 16 24 0 8 16 24 Effect of garlic on lipoprotein profile of APOE*3-Leiden mice Triglycerides Cholesterol Fractions

  18. Effect of garlic on blood pressure of APOE*3-Leiden mice 12 weeks 16 weeks 160 120 Blood pressure (mmHg) 80 40 0 Control 0.5% 5% Kyolic Control 0.5% 5% Kyolic Prin Prin Prin Prin

  19. Control Control Control Kyolic 0.5%Prin 5% Prin Effect of garlic on serum SAA and ICAM levels of APOE*3-Leiden mice 20 15 SAA (µg/ml) 10 5 0 0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 28 40 30 ICAM (µg/ml) 20 10 0 0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 28

  20. Control Control Control Kyolic 0.5%Prin 5% Prin Effect of garlic on plasma vWF levels of APOE*3-Leiden mice 250 200 150 vWF (% PP rat) 100 50 0 0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 28

  21. 250 200 150 100 50 0 Effect of garlic on atherosclerosis development of APOE*3-Leiden mice Cholesterol exposure Lesion typing Lesion area Type I-III Type IV-V 100 500 80 400 µm2 1000 mM 300 60 % 200 40 100 20 0 0 Control 0.5% 5% Kyolic Control 0.5% 5% Kyolic Control 0.5% 5% Kyolic Prin Prin Prin Prin Prin Prin

  22. Correlation between cholesterol exposure and atherosclerosis lesion area after garlic treatment of APOE*3-Leiden mice 600 Y= 0.8308x + 289.82 R= 0.8136 400 Cholesterol exposure (mM) 200 0 0 50 100 150 200 Area (µm2 1000)

  23. Conclusions 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.

  24. Future perspectives Human intervention study Collaboration with CHDR-Leiden

  25. Ackowledgements Sonia Espirito Santo Wim van Duyvenvoorde Erik Offerman Ria van den Hoogen Louis Havekes Hans Princen Bart van Vlijmen

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