title: Tobacco smoke regulates the expression and activity of microsomal prostaglandin E synthase-1: role of prostacyclin and NADPH-oxidase.
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) up-regulates 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.
authors: Centro Cardiologico Monzino, IRCCS, Via Parea 4, 20138 Milano, Italy. silviabarbieri@yahoo.com
authors: Silvia S
authors: SS
authors: Barbieri
authors: Patrizia
authors: P
authors: Amadio
authors: Sara
authors: S
authors: Gianellini
authors: Elena
authors: E
authors: Zacchi
authors: Babette B
authors: BB
authors: Weksler
authors: Elena
authors: E
authors: Tremoli
mesh_terms: D000818:Animals; D001593:Benzyl Compounds / Q000494:pharmacology; D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D007093:Imidazoles / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D000071876:Prostaglandin-E Synthases; D017382:Reactive Oxygen Species / Q000378:metabolism; D012906:Smoke / Q000009:adverse effects*
chemical_list: C514222:(2-(4-(4-isopropoxybenzyl)-phenylamino) imidazoline); D001593:Benzyl Compounds; D007093:Imidazoles; D053583:Interleukin-1beta; D017382:Reactive Oxygen Species; D012906:Smoke; C026678:carboprostacyclin; D011464:Epoprostenol; D019255:NADPH Oxidases; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse