Angiotensin II differentially modulates cyclooxygenase-2, microsomal prostaglandin E2 synthase-1 and prostaglandin I2 synthase expression in adventitial fibroblasts exposed to inflammatory stimuli

Aims 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)-1 beta]. Methods and results Fibroblasts stimulated with IL-1 beta (10 ng/ml, 24 h) and/or Ang II (0.1 mu mol/l, 24 h) were used. IL-1 beta up-regulated COX-2 and mPGES-1 (protein and mRNA) and increased PGI(2) and PGE(2) 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-1 beta-induced COX-2 expression and PGI(2) release and concomitantly reduced IL-1 beta-induced mPGES-1 expression. The AT(1) receptor antagonist losartan prevented the effects of Ang II on IL-1 beta-induced COX-2 or mPGES-1 expression. IL-1 beta 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-1 beta or the combination of IL-1 beta and Ang II. Ang II did not modify COX-2 transcriptional activity but increased COX-2 mRNA stability in IL-1 beta-treated cells; by contrast, it increased PGIS mRNA levels through a transcriptional mechanism. Conclusion Ang II differentially modulates key enzymes involved in prostanoid biosynthesis thereby altering the balance between PGI(2)/PGE(2) in vascular cells exposed to inflammatory stimuli. J Hypertens 29:529-536 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.