title: Angiotensin II differentially modulates cyclooxygenase-2, microsomal prostaglandin E2 synthase-1 and prostaglandin I2 synthase expression in adventitial fibroblasts exposed to inflammatory stimuli.
abstract: OBJECTIVE
  To assess whether angiotensin II (Ang II) modulates key enzymes of the cyclooxygenase (COX)-2/prostanoid pathway, including prostaglandin E synthase-1 (mPGES-1) and prostacyclin synthase (PGIS) in rat aortic adventitial fibroblasts in the presence or absence of an inflammatory stimulus [interleukin (IL)-1β].
  
  
  RESULTS
  Fibroblasts stimulated with IL-1β (10 ng/ml, 24 h) and/or Ang II (0.1 μmol/l, 24 h) were used. IL-1β up-regulated COX-2 and mPGES-1 (protein and mRNA) and increased PGI2 and PGE2 release, without altering PGIS protein expression. Ang II did modify neither COX-2 and mPGES-1 expression nor prostanoid levels, but it induced PGIS expression. Interestingly, Ang II further enhanced IL-1β-induced COX-2 expression and PGI2 release and concomitantly reduced IL-1β-induced mPGES-1 expression. The AT1 receptor antagonist losartan prevented the effects of Ang II on IL-1β-induced COX-2 or mPGES-1 expression. IL-1β activated p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK)1/2 pathways, and coincubation with Ang II resulted in a higher and more sustained phosphorylation of both MAPK. Inhibition of either p38 MAPK (SB203580) or ERK1/2 (PD98059) reduced COX-2 and mPGES-1 expression in cells treated with IL-1β or the combination of IL-1β and Ang II. Ang II did not modify COX-2 transcriptional activity but increased COX-2 mRNA stability in IL-1β-treated cells; by contrast, it increased PGIS mRNA levels through a transcriptional mechanism.
  
  
  CONCLUSIONS
  Ang II differentially modulates key enzymes involved in prostanoid biosynthesis thereby altering the balance between PGI2/PGE2 in vascular cells exposed to inflammatory stimuli.
authors.affiliation: Department de Farmacología, Universidad Autónoma de Madrid, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Spain.
authors.forename: María
authors.initials: M
authors.lastname: Galán
authors.forename: Marta
authors.initials: M
authors.lastname: Miguel
authors.forename: Amada E
authors.initials: AE
authors.lastname: Beltrán
authors.forename: Cristina
authors.initials: C
authors.lastname: Rodríguez
authors.forename: Ana B
authors.initials: AB
authors.lastname: García-Redondo
authors.forename: Ricardo
authors.initials: R
authors.lastname: Rodríguez-Calvo
authors.forename: María J
authors.initials: MJ
authors.lastname: Alonso
authors.forename: José
authors.initials: J
authors.lastname: Martínez-González
authors.forename: Mercedes
authors.initials: M
authors.lastname: Salaices
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D003238:Connective Tissue / Q000187:drug effects* / Q000201:enzymology; D051546:Cyclooxygenase 2 / Q000235:genetics*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology; D053583:Interleukin-1beta / Q000494:pharmacology*; D019746:Intramolecular Oxidoreductases / Q000235:genetics*; D008297:Male; D000071876:Prostaglandin-E Synthases; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D020871:RNA Stability; D051381:Rats; D017207:Rats, Sprague-Dawley; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: D053583:Interleukin-1beta; D000804:Angiotensin II; D003577:Cytochrome P-450 Enzyme System; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C497818:Ptges protein, rat; C022461:prostacyclin synthetase