Reduced thromboxane biosynthesis in carriers of toll-like receptor 4 polymorphisms in vivo.
The recent demonstration that platelets express a functional toll-like receptor 4 (TLR4) prompted us to explore the influence of TLR4 polymorphisms (Asp299Gly alone or in combination with Thr399Ile) on thromboxane A(2) (TXA(2)) biosynthesis in vivo. In 17 subjects with TLR4 polymorphisms versus 17 wild type (untreated with aspirin, matched for age, sex, and cardiovascular risk factors), intima-media thickness in the common carotid arteries was significantly lower. Average urinary excretion of 11-dehydro-TXB(2), an index of systemic biosynthesis of TX, was significantly reduced by 65%. The urinary excretion of 2,3-dinor-6-keto-prostaglandin F(1alpha), an index of systemic biosynthesis of prostacyclin, was marginally depressed but the prostacyclin/TXA(2) biosynthesis ratio was significantly higher than in wild type. Selective inhibition of cyclooxygenase 2-dependent prostacyclin (by rofecoxib or etoricoxib) was associated with increased urinary excretion of 11-dehydro-TXB(2) in carriers of TLR4 polymorphisms, but not in wild-type, suggesting a restrainable effect of prostacyclin on platelet function in vivo in this setting. Reduced TXA(2) biosynthesis may contribute to the protective cardiovascular phenotype of TLR4 polymorphisms.
Patrignani
Paola
P
Dipartimento di Medicina e Scienze, Dell'Invecchiamento, Università G. d'Annunzio, Via dei Vestini 31, 66013 Chieti, Italy. ppatrignani@unich.it
Di Febbo
Concetta
C
Tacconelli
Stefania
S
Moretta
Valeria
V
Baccante
Giovanna
G
Sciulli
Maria G
MG
Ricciotti
Emanuela
E
Capone
Marta L
ML
Antonucci
Ivana
I
Guglielmi
Maria D
MD
Stuppia
Liborio
L
Porreca
Ettore
E
D002318:Cardiovascular Diseases / Q000235:genetics / Q000517:prevention & control; D017536:Carotid Artery, Common / Q000000981:diagnostic imaging; D016022:Case-Control Studies; D011464:Epoprostenol / Q000096:biosynthesis; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D012307:Risk Factors; D013928:Thromboxane A2 / Q000096:biosynthesis*; D051197:Toll-Like Receptor 4 / Q000235:genetics*; D014463:Ultrasonography
C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D013928:Thromboxane A2; D011464:Epoprostenol