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.-Barbieri, S. S., Amadio, P., Gianellini, S., Zacchi, E., Weksler, B. B., Tremoli, E. Tobacco smoke regulates the expression and activity of microsomal prostaglandin E synthase-1: role of prostacyclin and NADPH-oxidase.

Tobacco smoke regulates the expression and activity of microsomal prostaglandin E synthase-1 : role of prostacyclin and NADPH-oxidase / S.S. Barbieri, P. Amadio, S. Gianellini, E. Zacchi, B.B. Weksler, E. Tremoli. - In: THE FASEB JOURNAL. - ISSN 0892-6638. - 25:10(2011 Oct), pp. 3731-3740. [10.1096/fj.11-181776]

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

S.S. Barbieri;P. Amadio;S. Gianellini;E. Zacchi;E. Tremoli
2011-10

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.-Barbieri, S. S., Amadio, P., Gianellini, S., Zacchi, E., Weksler, B. B., Tremoli, E. Tobacco smoke regulates the expression and activity of microsomal prostaglandin E synthase-1: role of prostacyclin and NADPH-oxidase.
prostanoids ; reactive oxygen species ; signal transduction ; smooth-cells ; cigarette-smoke ; endothelial-cells ; cyclooxygenase-2 expression ; superoxide generation ; vascular endothelium ; interleukin-1-beta ; atherosclerosis ; activation ; disease
Settore BIO/14 - Farmacologia
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/166920
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