PROSTAGLANDIN D-2 INHIBITS INDUCIBLE NITRIC-OXIDE SYNTHASE EXPRESSIONIN RAT VASCULAR SMOOTH-MUSCLE CELLS

Citation
H. Nagoshi et al., PROSTAGLANDIN D-2 INHIBITS INDUCIBLE NITRIC-OXIDE SYNTHASE EXPRESSIONIN RAT VASCULAR SMOOTH-MUSCLE CELLS, Circulation research, 82(2), 1998, pp. 204-209
Citations number
38
Categorie Soggetti
Hematology,"Peripheal Vascular Diseas
Journal title
ISSN journal
00097330
Volume
82
Issue
2
Year of publication
1998
Pages
204 - 209
Database
ISI
SICI code
0009-7330(1998)82:2<204:PDIINS>2.0.ZU;2-0
Abstract
Vascular smooth muscle cells (VSMCs) as well as macrophages have been shown to generate a substantial amount of NO in inflammatory vascular lesions. Prostaglandin (PG) D-2 (PGD(2)) is produced by inflammatory c ells, including mast cells and macrophages. We investigated whether PG D(2) modulates NO metabolism in rat VSMCs. PGD(2) at a concentration o f 10(-7) mol/L or greater dose-dependently inhibited nitrite accumulat ion in the medium of cultured VSMCs stimulated with interleukin 1 beta (IL-1 beta). In a dose-response analysis of IL-1 beta and nitrite acc umulation, PGD(2) was seen to decrease the maximal ability of VSMCs to generate NO, arguing against competition by PGD(2) at cytokine recept ors. Northern analysis showed that PGD(2) suppresses induction of indu cible NO synthase (iNOS) mRNA in Il-1 beta-stimulated VSMCs, with cons equent inhibition of iNOS protein expression in Western analysis. A th romboxane A(2) (TXA(2)) analogue, U46619 (10(-5) mol/L), produced less inhibition of NO generation than did PGD(2). Neither the PGI(2) analo g carbaprostacyclin nor PGE(1) showed any inhibition. PGD(2) dose-depe ndently inhibited NO generation despite the addition of the TXA(2) ant agonist SQ29548, PGJ(2), Delta(12)-PGJ(2), and 15-deoxy-Delta(12,14)-P GJ(2), all metabolites of PGD(2) were as potent as or slightly stronge r than PGD(2) in the inhibition of NO generation. These data suggest t hat PGD(2) suppresses NO generation in VSMCs by inhibiting iNOS mRNA e xpression, most likely through the cascade of the PGJ(2) series rather than through the TX receptor or cAMP upregulation. Such action makes it likely that PGD(2) regulates NO metabolism in vascular lesions.