Endothelium is a highly dynamic tissue that regulates numerous physiological and pathological functions to preserve permeability, vasodilation and anti-thrombotic properties of the vessel wall. This unique feature requires a constant adaptive rearrangement of endothelial cells, either in terms of shape or function that cannot set aside the role of cytoskeleton. Here, we show that nocodazole, a microtubule disrupting agent, strongly up-regulates cyclooxygenase-2 (Cox-2) expression in human endothelial cells, in close association with gap formation. In parallel, the levels of acetylated α- tubulin, marker of microtubule stability, were reduced. All these effects were prevented by the microtubule stabilizer paclitaxel, relating them to the disruption of the tubular network. In addition, nocodazole diminished the intracellular ratio of reduced to oxidized glutathione (GSH/GSSG) and increased the extent of glutathionylated actin with concomitant dissolution of F-actin cortical ring and stress fiber formation. Either the antioxidant N- acetylcysteine (NAC) or exogenous GSH reduced Cox-2 levels and preserved the integrity of the endothelial monolayer. Similarly, the Cox-2 metabolite prostacyclin (PGI2) down-regulated Cox-2 levels through a receptor-mediated mechanism, and restored cell monolayer. In a quest for signalling molecules that connect microtubule disruption to Cox-2 induction, we identified Src family kinase activity, serine/threonine phosphatase 2A inhibition, and phosphorylation of mitogen activated protein kinase p38 (p38 MAPK) as essential. Overall, data link alterations in microtubule and actin cytoskeleton to Cox-2 expression in human endothelial cells and provide a molecular basis for the observation that Cox-2 is up-regulated by mechanical stress to promote an adaptive response for the maintenance of the vasodilatory and antithrombotic properties of the vessel wall.
Cytoskeletal architecture regulates cyclooxygenase-2 in human endothelial cells / S. Eligini, V. Cavalca, P. Songia, M. Crisci, E. Tremoli, S. Colli. - In: BLOOD TRANSFUSION. - ISSN 1723-2007. - 8:suppl. 4(2010 Dec), pp. s55-s55. ((Intervento presentato al 21. convegno Congresso Nazionale SISET tenutosi a Bologna nel 2010.
|Titolo:||Cytoskeletal architecture regulates cyclooxygenase-2 in human endothelial cells|
ELIGINI, SONIA (Primo)
CAVALCA, VIVIANA MARIA (Secondo)
TREMOLI, ELENA (Penultimo)
COLLI, SUSANNA (Ultimo)
|Settore Scientifico Disciplinare:||Settore BIO/12 - Biochimica Clinica e Biologia Molecolare Clinica|
Settore BIO/14 - Farmacologia
|Data di pubblicazione:||dic-2010|
|Enti collegati al convegno:||Societa' Italiana per lo Studio dell'Emostasi e della Trombosi (SISET)|
|Appare nelle tipologie:||01 - Articolo su periodico|