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 1 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(2) and the synergistic effect of iloprost and phorbolester on PGI(2) 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.
Debey
Svenja
S
Institut für Pharmakologie und Klinische Pharmakologie, Universitäts Klinikum Düsseldorf, Heinrich-Heine-Universität, Moorenstrasse 5, D-40225 Düsseldorf, Germany.
Meyer-Kirchrath
Jutta
J
Schrör
Karsten
K
D000242:Cyclic AMP / Q000378:metabolism; D051786:Cyclic AMP Response Element Modulator; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology*; D051546:Cyclooxygenase 2; D004268:DNA-Binding Proteins / Q000502:physiology*; D011464:Epoprostenol / Q000096:biosynthesis; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D016285:Iloprost / Q000494:pharmacology*; D007527:Isoenzymes / Q000096:biosynthesis*; D008565:Membrane Proteins; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D012097:Repressor Proteins; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors; D014665:Vasodilator Agents / Q000494:pharmacology
D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D014665:Vasodilator Agents; D051786:Cyclic AMP Response Element Modulator; D011464:Epoprostenol; D000242:Cyclic AMP; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D016285:Iloprost; D013755:Tetradecanoylphorbol Acetate