Regulation of cyclooxygenase-2 expression by iloprost in human vascular smooth muscle cells -: Role of transcription factors CREB and ICER

Prostaglandin-endoperoxide synthase-2 (PGH-synthase) or cyclooxygenase-2 (COX-2) is inducible by a variety of stimuli, e.g. inflammatory mediators, growth factors and hormones and is believed to be responsible for the majority of inflammatory prostanoid production. Moreover, it has been demonstrated that COX-2 contributes substantially to prostacyclin-synthesis in patients with atherosclerosis. In this study, we demonstrate an up-regulation of COX-2 mRNA, protein and product formation by the prostacyclin-mimetic iloprost in human vascular smooth muscle cells (hSMC). COX-2 mRNA expression was induced transiently between I and 6 hr and returned to basal levels after 16 hr of iloprost stimulation. COX-2 protein was induced concomitantly between 3 and 6 hr of iloprost stimulation. This was accompanied by an increase in PGI(2) formation. Forskolin, a direct activator of adenylyl cyclase, and dibutyryl cAMP, a cell-permeable cAMP analogue-induced COX-2 mRNA, suggesting a cAMP-dependent COX-2 expression in hSMC. Iloprost-induced COX-2 protein expression and PGI(2) formation was synergistically elevated by co-stimulation with the phorbolester PMA (phorbol-12-myristate-13-acetate). It is concluded, that the observed up-regulation of COX-2 with subsequent release of newly synthesized PGI, and the synergistic effect of iloprost and phorbolester on PGI, formation provide a positive feedback of prostaglandins on their own synthesizing enzyme. This might be important for control of hSMC proliferation, migration and differentiation as well as inhibition of platelet aggregation. (C) 2003 Elsevier Science Inc. All rights reserved.