title: Reduced thromboxane biosynthesis in carriers of toll-like receptor 4 polymorphisms in vivo.
abstract: 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.
authors.affiliation: Dipartimento di Medicina e Scienze, Dell'Invecchiamento, Università G. d'Annunzio, Via dei Vestini 31, 66013 Chieti, Italy. ppatrignani@unich.it
authors.forename: Paola
authors.initials: P
authors.lastname: Patrignani
authors.forename: Concetta
authors.initials: C
authors.lastname: Di Febbo
authors.forename: Stefania
authors.initials: S
authors.lastname: Tacconelli
authors.forename: Valeria
authors.initials: V
authors.lastname: Moretta
authors.forename: Giovanna
authors.initials: G
authors.lastname: Baccante
authors.forename: Maria G
authors.initials: MG
authors.lastname: Sciulli
authors.forename: Emanuela
authors.initials: E
authors.lastname: Ricciotti
authors.forename: Marta L
authors.initials: ML
authors.lastname: Capone
authors.forename: Ivana
authors.initials: I
authors.lastname: Antonucci
authors.forename: Maria D
authors.initials: MD
authors.lastname: Guglielmi
authors.forename: Liborio
authors.initials: L
authors.lastname: Stuppia
authors.forename: Ettore
authors.initials: E
authors.lastname: Porreca
mesh_terms: 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
chemical_list: C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D013928:Thromboxane A2; D011464:Epoprostenol