Tobacco smoke regulates the expression and activity of microsomal prostaglandin e synthase-1: Role of prostacyclin and NADPH-oxidase

Silvia S. Barbieri, Patrizia Amadio, Sara Gianellini, Elena Zacchi, Babette B. Weksler, Elena Tremoli

Research output: Contribution to journalArticlepeer-review

Abstract

Tobacco smoke (TS) interacts with interleukin- 1β (IL-1β) to modulate generation of reactive oxygen species (ROS) and expression of cyclooxygenase-2. We explored molecular mechanisms by which TS/ IL-1β alters expression and activity of microsomal-prostaglandin E synthase-1 (mPGES-1) and of prostacyclin synthase (PGIS) in mouse cardiac endothelial cells. TS (EC 50 ∼5 puffs/L) interacting with IL-1β (2 μg/L) upregulates PGE 2 production and mPGES-1 expression, reaching a plateau at 4-6 h, but down-regulates prostacyclin (PGI 2) release by increasing IL-1β-mediated PGIS tyrosine nitration. Inhibition of NADPH-oxidase, achieved pharmacologically and/or by silencing its catalytic subunit p47phox, or exogenous PGI 2 (carbaprostacyclin; IC 50 ∼5 μM) prevents production of both ROS and PGE 2, and negatively modulates mPGES-1 expression induced by TS/IL-1β. Moreover, inhibiting PGI 2, either using PGIS siRNA and/or CAY10441 (EC 50 ∼20 nM), a PGI 2 receptor antagonist, increases NADPH-oxidase activation, mPGES-1 synthesis, and PGE 2 production. Finally, lower PGI 2 levels associated with higher PGIS tyrosine nitration, p47phox translocation to the membrane (an index of activation of NADPH-oxidase), and mPGES-1 expression and activity were detected in cardiovascular tissues of ApoE -/- mice exposed to cigarette smoke compared to control mice. In conclusion, cigarette smoke in association with cytokines alters the balance between PGI 2/PGE 2, reducing PGI 2 production and increasing synthesis and activity of mPGES-1 via NADPH-oxidase activation, predisposing to development of pathological conditions.

Original languageEnglish
Pages (from-to)3731-3740
Number of pages10
JournalFASEB Journal
Volume25
Issue number10
DOIs
Publication statusPublished - Oct 2011

Keywords

  • Endothelial cells
  • Prostanoids
  • Reactive oxygen species
  • Signal transduction

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

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