title: Production of prostaglandin E2 induced by cigarette smoke modulates tissue factor expression and activity in endothelial cells.
abstract: Cigarette smoke (CS) increases the incidence of atherothrombosis, the release of prostaglandin (PG) E2, and the amount of tissue factor (TF). The link between PGE2 and TF, and the impact of this interaction on CS-induced thrombosis, is unknown. Plasma from active smokers showed higher concentration of PGE2, TF total antigen, and microparticle-associated TF (MP-TF) activity compared with never smokers. Similar results were obtained in mice and in mouse cardiac endothelial cells (MCECs) after treatment with aqueous CS extracts (CSEs) plus IL-1β [CSE (6.4 puffs/L)/IL-1β (2 μg/L)]. A significant correlation between PGE2 and TF total antigen or MP-TF activity were observed in both human and mouse plasma or tissue. Inhibition of PGE synthase reduced TF in vivo and in vitro and prevented the arterial thrombosis induced by CSE/IL-1β. Only PG E receptor 1 (EP1) receptor antagonists (SC51089:IC50 ∼ 1 μM, AH6809:IC50 ∼ 7.5 μM) restored the normal TF and sirtuin 1 (SIRT1) levels in MCECs before PGE2 (EC50 ∼ 2.5 mM) or CSE/IL-1β exposure. Similarly, SIRT1 activators (CAY10591: IC50 ∼ 10 μM, resveratrol: IC50 ∼ 5 μM) or prostacyclin analogs (IC50 ∼ 5 μM) prevented SIRT1 inhibition and reduced TF induced by CSE/IL-1β or by PGE2. In conclusion, PGE2 increases both TF expression and activity through the regulation of the EP1/SIRT1 pathway. These findings suggest that EP1 may represent a possible target to prevent prothrombotic states.
authors.affiliation: *Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy; Centro Cardiologico Monzino, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy; and Division of Hematology-Medical Oncology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Amadio
authors.affiliation: *Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy; Centro Cardiologico Monzino, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy; and Division of Hematology-Medical Oncology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Damiano
authors.initials: D
authors.lastname: Baldassarre
authors.affiliation: *Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy; Centro Cardiologico Monzino, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy; and Division of Hematology-Medical Oncology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Tarantino
authors.affiliation: *Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy; Centro Cardiologico Monzino, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy; and Division of Hematology-Medical Oncology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Zacchi
authors.affiliation: *Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy; Centro Cardiologico Monzino, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy; and Division of Hematology-Medical Oncology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Gianellini
authors.affiliation: *Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy; Centro Cardiologico Monzino, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy; and Division of Hematology-Medical Oncology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Isabella
authors.initials: I
authors.lastname: Squellerio
authors.affiliation: *Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy; Centro Cardiologico Monzino, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy; and Division of Hematology-Medical Oncology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Mauro
authors.initials: M
authors.lastname: Amato
authors.affiliation: *Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy; Centro Cardiologico Monzino, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy; and Division of Hematology-Medical Oncology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Babette B
authors.initials: BB
authors.lastname: Weksler
authors.affiliation: *Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy; Centro Cardiologico Monzino, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy; and Division of Hematology-Medical Oncology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Tremoli
authors.affiliation: *Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy; Centro Cardiologico Monzino, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy; and Division of Hematology-Medical Oncology, Weill Cornell Medical College, New York, New York, USA silvia.barbieri@ccfm.it.
authors.forename: Silvia S
authors.initials: SS
authors.lastname: Barbieri
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015232:Dinoprostone / Q000097:blood*; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D053583:Interleukin-1beta / Q000097:blood; D008297:Male; D051379:Mice; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010077:Oxazepines / Q000494:pharmacology; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects / Q000097:blood* / Q000473:pathology; D013925:Thromboplastin / Q000096:biosynthesis*; D013927:Thrombosis / Q000097:blood* / Q000209:etiology; D044004:Xanthones / Q000494:pharmacology
chemical_list: D006834:Hydrazines; C508585:IL1B protein, human; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D010077:Oxazepines; D044004:Xanthones; C086836:SC 51089; C053876:6-isopropoxy-9-oxoxanthene-2-carboxylic acid; D013925:Thromboplastin; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D015232:Dinoprostone
keywords: EP1 receptor; SIRT1; prostanoids; thrombosis