Processo infiammatorioProcesso infiammatorio

arteria arteria normalenormale

attivazione attivazione endotelialeendoteliale

progressioneprogressione

strie strie lipidichelipidiche

ateroma ateroma intramurale intramurale

maturomaturo

complicanzecomplicanze

rottura rottura cappa cappa fibrosafibrosa

placca placca fibrosa/ fibrosa/ calcificacalcifica

erosione erosione endotelialeendoteliale

STENOSISTENOSITROMBOSITROMBOSI TROMBOSITROMBOSIRIMODELLAMENTORIMODELLAMENTO

The mevalonate pathway

Acetyl-CoA

HMG-CoA

Mevalonate

Farnesyl-PP

Squalene

Cholesterol

Geranylgeranyl Transferase

Farnesyl Transferase

HMG-CoA Reductase Statins

Farnesylated proteins

Trans Trans Geranygeranyl-PP

Ubiquinones

Dolichols

Geranylgeranylatedprotein

The Mevalonate The Mevalonate PathwayPathwayAcetyl-CoA

HMG-CoA

Mevalonate

Isopentenyl-PP

Geranyl-PP

Farnesyl-PP

Prenylated Proteins

HMG-CoA Reductase Statins

Dolichols

2-cis Geranylgeranyl-PP

all-trans Geranylgeranyl-PP

Ubiquinone

Squalene

Cholesterol

X

Rex A. Parker et al, The Journal of Biological Chemistry 1993;Nov. 6:11230-11238

-Tocotrienol decrease incorporation of acetate but not mevalonate into cholesterol in HepG2 cells

Rex A. Parker et al, The Journal of Biological Chemistry 1993;Nov. 6:11230-11238

Suppression of HMG-CoA reductase total activity correlates with inhibition of cholesterol synthesis by -tocotrienol in HepG2 cells

A. Theriault et al., Clinical Biochemistry 1999;Vol 32:309-319

Mechanism of the cholesterol suppressive action of tocotrienol

+

--

A. Theriault et al., Clinical Biochemistry 1999;Vol 32:309-319

Mechanism for the reduction in low density lipoprotein (LDL) by tocotrienol

Asaf A. Qureshi et al., Atherosclerosis 2002;161:199-207

Effects of of Tocotrienol-Rich Fraction (TRF25) on serum lipid parameters in hypercolesterolemic human subjects

Asaf A. Qureshi et al., Journal of Nutritional Biochemistry 2001;12:318-329

Synergistic effect of of Tocotrienol-Rich Fraction (TRF25) and lovastatin

Asaf A. Qureshi et al., Journal of Nutritional Biochemistry 2001;12:318-329

Serum lipid parameters in GROUP A

Asaf A. Qureshi et al., Journal of Nutritional Biochemistry 2001;12:318-329

Serum lipid parameters in GROUP B

Formazione della Placca AteroscleroticaFormazione della Placca AteroscleroticaAttivazione endoteliale

up-regulation molecole di adesione

migrazione leucocitaria

aumentata

permeabilità endoteliale

Shear stressintermittente

F.di R.LDL

Molecole di Adesione Selectine Immunoglobuline endoteliali

Chemoattrattanti Chemochine

Infiammazione

formazione “strie

lipidiche”

migrazione cellule

muscolari lisce

ingrandimento nucleo lipidico

LDL

Fattori di Crescita Grow Factors

Formazione della Placca Formazione della Placca AteroscleroticaAterosclerotica

“ lesione intermedia”

Infiammazione

FormazioneFormazione della Placca Ateroscleroticadella Placca Aterosclerotica

Enzimi litici – Fattori della CoagulazioneMetalloproteinasi

“ lesione avanzata”

Infiammazione

assottigliamento del

cappuccio fibroso

(erosione)rottura della

placca (shoulder region)

TROMBOSI

F.di R.LDL

Fattore Tissutale

The mevalonate pathway

Acetyl-CoA

HMG-CoA

Mevalonate

Farnesyl-PP

Squalene

Cholesterol

Geranylgeranyl Transferase

Farnesyl Transferase

HMG-CoA Reductase Statins

Farnesylated proteins

Trans Trans Geranygeranyl-PP

Ubiquinones

Dolichols

Geranylgeranylatedprotein

The Mevalonate The Mevalonate PathwayPathwayAcetyl-CoA

HMG-CoA

Mevalonate

Isopentenyl-PP

Geranyl-PP

Farnesyl-PP

Prenylated Proteins

HMG-CoA Reductase Statins

Dolichols

2-cis Geranylgeranyl-PP

all-trans Geranylgeranyl-PP

Ubiquinone

Squalene

Cholesterol

X

A. Theriault et al., Atherosclerosis 2002;160:21-30

Concentration dependent effects of -Tocotrienol on VCAM-1 expression in cultured endothelial cells

A. Theriault et al., Atherosclerosis 2002;160:21-30

Effects of -Tocotrienol on VCAM-1, ICAM-1 and E-selectin expressionin in cultured endothelial cells

A. Theriault et al., Atherosclerosis 2002;160:21-30

Effects of -tocotrienol and analogs on

the adherence of monocytes to HUVEC

A. Theriault et al., Atherosclerosis 2002;160:21-30

Effect of farnesol and geranylgeraniol on the inhibitor effect of -tocotrienol on monocyte adherence to HUVEC

Asaf A. Qureshi et al., J Nutr 2001;131:2606-2618

Effect of -tocopherol, Tocotrienol-Rich Fraction (TRF25), and didesmethyl tocotrienol (d-P25-T3) on total and LDL cholesterol in

C57BL/6 apoE mice

Asaf A. Qureshi et al., J Nutr 2001;131:2606-2618

Effect of -tocopherol, Tocotrienol-Rich Fraction (TRF25), and didesmethyl tocotrienol (d-P25-T3) on esperimental atherosclerotic

plaque formation

A. Theriault et al., Clinical Biochemistry 1999;Vol 32:309-319

Mechanism by which tocotrienol inhibits

the generation of foam cells

Randomised controlled trial of Tocopherol in pateints with coronary disease: Cambridge Heart Antioxidant Study (CHAOS)

N.G. Stephens et al, Lancet, 1996; Vol 347, 781-86

Randomised controlled trial of Tocopherol in pateints with coronary disease: Cambridge Heart Antioxidant Study (CHAOS)

N.G. Stephens et al, Lancet, 1996; Vol 347, 781-86

Randomised controlled trial of Tocopherol in pateints with coronary disease: Cambridge Heart Antioxidant Study (CHAOS)

N.G. Stephens et al, Lancet, 1996; Vol 347, 781-86

A. Theriault et al., Atherosclerosis 2002;160:21-30

Effects of -Tocotrienol and analogs on the expression of adhesion molecules in cultured endothelial cells

-TS: -tocopheryl succinate-T: -tocopherol-T3: -tocotrienol

R. Ricciarelli et al., Circulation 2000;102:82-87

-tocopherol reduces CD36 scavenger receptor expression in smooth muscle cells

S. Devaraj et al., J Lipid Res 2001;42:521-527

-tocopherol reduces CD36 scavenger receptor expression in monocyte-derived macrophages

AT: -tocopherol

S. Devaraj et al., J Lipid Res 2001;42:521-527

Effect of -tocopherol on AcLDL- and OxLDL-induced CD36 scavenger receptor expression

S. Devaraj et al., J Lipid Res 2001;42:521-527

Effect of -tocopherol on cholesteryl ester

accumulation in macrophages

Processo infiammatorioProcesso infiammatorio

arteria arteria normalenormale

attivazione attivazione endotelialeendoteliale

progressioneprogressione

strie strie lipidichelipidiche

ateroma ateroma intramurale intramurale

maturomaturo

complicanzecomplicanze

rottura rottura cappa cappa fibrosafibrosa

placca placca fibrosa/ fibrosa/ calcificacalcifica

erosione erosione endotelialeendoteliale

STENOSISTENOSITROMBOSITROMBOSI TROMBOSITROMBOSIRIMODELLAMENTORIMODELLAMENTO