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Circulation Research. 1998;82:204-209

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(Circulation Research. 1998;82:204-209.)
© 1998 American Heart Association, Inc.

Original Contributions

Prostaglandin D2 Inhibits Inducible Nitric Oxide Synthase Expression in Rat Vascular Smooth Muscle Cells

Hiroshi Nagoshi, Yoshio Uehara, Fumihiko Kanai, Shin Maeda, Tsutomu Ogura, Atsuo Goto, Teruhiko Toyo-oka, Hiroyasu Esumi, Takao Shimizu, , Masao Omata

From the Second Department of Internal Medicine (H.N., Y.U., F.K., S.M., A.G., T.T., M.O.) and the Department of Biochemistry (T.S.), University of Tokyo; and the Biochemistry Division (T.O., H.E.), National Cancer Center Research Institute, Tokyo, Japan.

Correspondence to Hiroshi Nagoshi, MD, The Second Department of Internal Medicine, University of Tokyo, 7–3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan.

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) D2 (PGD2) is produced by inflammatory cells, including mast cells and macrophages. We investigated whether PGD2 modulates NO metabolism in rat VSMCs. PGD2 at a concentration of 10–7 mol/L or greater dose-dependently inhibited nitrite accumulation in the medium of cultured VSMCs stimulated with interleukin 1ß (IL-1ß). In a dose-response analysis of IL-1ß and nitrite accumulation, PGD2 was seen to decrease the maximal ability of VSMCs to generate NO, arguing against competition by PGD2 at cytokine receptors. Northern analysis showed that PGD2 suppresses induction of inducible NO synthase (iNOS) mRNA in IL-1ß–stimulated VSMCs, with consequent inhibition of iNOS protein expression in Western analysis. A thromboxane A2 (TXA2) analogue, U46619 (10–5 mol/L), produced less inhibition of NO generation than did PGD2. Neither the PGI2 analog carbaprostacyclin nor PGE1 showed any inhibition. PGD2 dose-dependently inhibited NO generation despite the addition of the TXA2 antagonist SQ29548. PGJ2, {Delta}12-PGJ2, and 15-deoxy-{Delta}12,14-PGJ2, all metabolites of PGD2, were as potent as or slightly stronger than PGD2 in the inhibition of NO generation. These data suggest that PGD2 suppresses NO generation in VSMCs by inhibiting iNOS mRNA expression, most likely through the cascade of the PGJ2 series rather than through the TX receptor or cAMP upregulation. Such action makes it likely that PGD2 regulates NO metabolism in vascular lesions.


Key Words: inducible nitric oxide synthase • prostaglandin D2 • vascular smooth muscle cells {blacksquare} expression inhibition • prostaglandin J2




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