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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. L University Medical Center Department of Cardiology The Netherlands. Garlic and health.

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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 L University Medical Center Department of Cardiology The Netherlands

  2. Garlic and health • Garlic has an history for its use in cardiovascular medicine. • Some studies have suggested that garlic significantly reduces plasma lipid levels, systolic and diastolic blood pressure and that it shows a strong antibiotic activity. Kik C, Kahane R, Gebhardt R. Nutr Metab Cardiovasc Dis. 2001;11:57-65. • Clinical trials and animal studies with well-characterized and standardized garlic material, with a consistent study design and dosage are scarcely found in the last 15 years.

  3. LDL SYNTHESIS UPTAKE LIVER CHOLESTEROL STORAGE CHOLESTERYL ESTERS VLDL BILE ACIDS BILIARY CHOLESTEROL INTESTINE CM Remnants DIETARY CHOLESTEROL CM Possible effects of garlic on lipid metabolism

  4. Intima Fibrous cap Media Monocytes Thrombus LDL Endothelium oxLDL O2 Lipid core Collagen- degrading proteinases Possible effects of garlic on atherosclerosis SHEAR STRESS INFLAMMATION OXIDATION

  5. Contradictory effects in garlic studies • Old human trials in hypercholesterolemic patients reported a decrease in plasma lipid levels. Jain et al, 1993. Silagy et al, 1994. Steiner et al, 1996. Bordia et al, 1997. • Recent human trials in hypercholesterolemic patients showed no effects of garlic treatment on plasma lipids. Simmons et al,1994. Neil et al, 1996. Breithaupt et al, 1997. Berthold et al, 1998. McCrindle et al, 1998. Isaacsohn et al, 1998. Gardner et al, 2001. Ziaei et al, 2001. Phelps et al, 1998. Satitvipawee et al, 2003. • Induced-atherosclerosis in rabbits kyolic showed a decrease in aortic fatty streaks-like lesions. Efendy JL, et al. Atherosclerosis. 1997:132:37-42. Campbell JH, et al. J Nutr. 2001;131:1006S-09S. • Allicin treatment in hypercholesterolemic C57Black/6 mice showed no effects on plasma lipid levels and decreased aortic fatty streak-like lesions. D. Abramovitz et al., Coronary Artery Disease, 1999, 10: 515-519. • Hypercholesterolemic pigs and rats fed garlic oil and garlic powder (Kwai) showed no effects on atherosclerosis. Heinle H,et al. Drug Res. 1994;44:614-17. Lee WM, et al. Exper Mol Pathol. 1980:33:345-8.

  6. Previous reported effects of garlic (Kwai, Morado, Allicin and DADS) in APOE*3-Leiden mice • Lipid metabolism • No effects of Kwai, Morado, Allicin and DADS on plasma lipid levels and markers of cholesterol synthesis and absorption under hyperlipidemic conditions. • Morado garlic powder showed an improved liver function, decreased plasma cholesterol levels and serum amyloid A levels under severe atherogenic conditions. • Severe 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.

  7. 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.

  8. Effect of garlic on inflammation and atherosclerosis under human-like conditions: Garlic powders • Printanor FR 2001: 0.5% of dry garlic powder (low sulfur content) • Printanor FR 2001: 5% of dry garlic powder (low sulfur content) • Kyolic (positive control): 0.16% Previously 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.

  9. 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: General 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, total lesion area, and monocytes adhesion.

  10. Effect of garlic on body weight gain in 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

  11. Effect of garlic on food intake and plasma free fatty acids in 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 *P<0.05

  12. Effect of garlic on fecal fatty acids excretion in 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

  13. Effect of garlic on liver function in 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

  14. Effect of garlic on plasma cholesterol levels in 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

  15. Effect of garlic on plasma triglyceride levels in 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

  16. 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 in APOE*3-Leiden mice Triglycerides Cholesterol Fractions

  17. Effect of garlic on blood pressure in 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

  18. Control Control Control Kyolic 0.5%Prin 5% Prin Effect of garlic on serum SAA and ICAM levels in 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

  19. Control Control Control Kyolic 0.5%Prin 5% Prin Effect of garlic on plasma vWF levels in 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

  20. 60 * * * * * * Standard diet 40 Atherogenic diet Control 0.5% Prin TNF (pg/ml) 5% Prin 20 Kyolic 10 0 150 0 50 100 LPS (ng/ml) Effect of garlic on whole blood TNF levels in response to LPS in APOE*3-Leiden mice *P<0.05

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

  22. Monocytes adhesion Lesion area 250 50 200 40 µm2 x1000 150 30 # monocytes 100 20 50 10 0 0 Control 0.5% 5% Kyolic Control 0.5% 5% Kyolic Prin Prin Prin Prin Effect of garlic on atherosclerosis development in APOE*3-Leiden mice

  23. Conclusions (1) 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.

  24. Conclusions (2) Dietary garlic treatment in APOE*3-Leiden mice results in: • No effects on the TNF production by monocytes in response to incubation with LPS, in an ex vivo whole blood assay. Garlic did not affect the activation status of circulating monocytes. • No effects on markers of general and vessel wall inflammation, and on atherosclerosis development.

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

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

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