Production of prostaglandin E2 induced by cigarette smoke modulates tissue factor expression and activity in endothelial cells

Patrizia Amadio, Damiano Baldassarre, Eva Tarantino, Elena Zacchi, Sara Gianellini, Isabella Squellerio, Mauro Amato, Babette B. Weksler, Elena Tremoli, Silvia S. Barbieri

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)4001-4010
Number of pages10
JournalFASEB Journal
Volume29
Issue number9
DOIs
Publication statusPublished - Sep 1 2015

Keywords

  • EP1 receptor
  • prostanoids
  • SIRT1
  • thrombosis

ASJC Scopus subject areas

  • Medicine(all)

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