Endothelium is a highly dynamic tissue that governs physiological and pathological functions to preserve permeability, vasodilation and the anti-thrombotic properties of the vessel wall. As a result of their unique location, endothelial cells are exposed to a highly dynamic environment that requires a constant rearrangement, either in terms of morphology or function, to maintain an intact monolayer at rest and re-establishing it after disruption. Adaptive physiologic/pathophysiologic responses that are either systematically or regionally compromised by hyperlipidemia, hypertension, diabetes and inflammatory disorders, depend upon the function of cytoskeleton. Obviously, cytoskeletal alterations impact signalling pathways that regulate the expression of genes involved in endothelial “reprogramming”. In this respect, the microtubule-targeted drugs are considered useful tools for the identification of cytoskeletal sensitive genetic responses and for the clarification of signalling pathways associated with alteration of cytoskeletal integrity (Samarakoon et al., 2002). Arachidonic acid metabolites are important in the modulation of vascular homeostasis. The major rate-limiting enzymes involved in their synthesis are the cyclooxygenases: cyclooxygenase-1 is constitutively expressed in most tissues and has general housekeeping functions, whereas cyclooxygenase-2 (Cox-2) is responsible for high-level production of prostanoids in response to pro-inflammatory agents, tumor promoters and growth factors. Cox-2 activity may serve as a compensatory mechanism to preserve vasodilation and the anti-thrombotic properties of the vessel wall under damaging conditions (Cheng et al., 2002). Indeed, Cox-2 metabolites, particularly prostacyclin (PGI2) and prostaglandin E2 (PGE2), have profound influences on vascular tone, platelet activation, permeability and remodeling, angiogenesis and wound repair (Turini et al., 2002). Here, we show that nocodazole, a microtubule disrupting agent, strongly up-regulates Cox-2 in human endothelial cells, in close association with gap formation. In parallel, the levels of acetylated -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 increased the extent of glutathionylated actin with dissolution of F-actin cortical ring and stress fiber formation. Concomitantly, intracellular GSH levels were reduced. Of note, the Cox-2 metabolite prostacyclin (PGI2) down-regulated Cox-2 levels through a receptor-mediated mechanism, and restored, at least in part, the monolayer integrity. In a quest for signaling molecules that connect microtubule disruption to Cox-2 induction, we identified serine/threonine phosphatase 2A inhibition and phosphorylation of mitogen activated protein kinase p38 (p38 MAPK) as essential. Taken together data link alterations in microtubule and actin cytoskeleton to Cox-2 expression in human endothelial cells. This finding may represent a mechanistic perspective that set Cox-2 among the endothelial genes whose up-regulation by atherogenic/inflammatory agents is mediated by perturbation of cytoskeletal integrity. In this respect, Cox-2 expression in dysfunctional endothelial cells can be viewed as compensatory in virtue of the atheroprotective properties of PGI2. Samarakoon et al., (2002) J Cell Sci 115:3093-103. Cheng et al., (2002) Science 296:539-41. Turini et al., (2002) Annu Rev Med 53:35-57.
Cytoskeleton and cyclooxigenase -2 expression in human endothelial cells: autocrine modulation by prostacyclin / S. Eligini, V.M. Cavalca, P. Songia, M. Crisci, E. Tremoli, S. Colli. ((Intervento presentato al 35. convegno Congresso Nazionale SIF tenutosi a Bologna nel 2011.
|Titolo:||Cytoskeleton and cyclooxigenase -2 expression in human endothelial cells: autocrine modulation by prostacyclin|
ELIGINI, SONIA (Primo)
CAVALCA, VIVIANA MARIA (Secondo)
TREMOLI, ELENA (Penultimo)
COLLI, SUSANNA (Ultimo)
|Data di pubblicazione:||2011|
|Settore Scientifico Disciplinare:||Settore BIO/12 - Biochimica Clinica e Biologia Molecolare Clinica|
Settore BIO/14 - Farmacologia
|Citazione:||Cytoskeleton and cyclooxigenase -2 expression in human endothelial cells: autocrine modulation by prostacyclin / S. Eligini, V.M. Cavalca, P. Songia, M. Crisci, E. Tremoli, S. Colli. ((Intervento presentato al 35. convegno Congresso Nazionale SIF tenutosi a Bologna nel 2011.|
|Appare nelle tipologie:||14 - Intervento a convegno non pubblicato|