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  • Title: Downregulation of nitric oxide accumulation by cyclooxygenase-2 induction and thromboxane A2 production in interleukin-1beta-stimulated rat aortic smooth muscle cells.
    Author: Shiokoshi T, Ohsaki Y, Kawabe J, Fujino T, Kikuchi K.
    Journal: J Hypertens; 2002 Mar; 20(3):455-61. PubMed ID: 11875313.
    Abstract:
    BACKGROUND: Cytokines from inflammatory cells do not produce nitric oxide, but stimulate the production of nitric oxide in vascular smooth muscle cells (VSMC). Thromboxane A2 (TXA2) has been believed to have a key role in atherosclerogenesis and post-angioplasty restenosis. OBJECTIVE: To determine whether cytokine-induced nitric oxide production is regulated by the TXA2/prostaglandin H2 (PGH2) receptor. METHODS AND RESULTS: We studied the interleukin-1beta (IL-1beta)-induced production of nitric oxide in rat VSMCs using the TXA2/PGH2 receptor antagonists, seratrodast and Bay-u3405, and an agonist, U-46619. Nitrite formation was measured colorimetrically. IL-1beta increased nitrite formation in a time-dependent manner. The nitrite concentration was 1.7 times greater in the presence of seratrodast than that without it. Nitrite accumulation was increased by Bay-u3405, but was decreased in the presence of U-46619, to 44% of that in its absence. Western and Northern blotting showed that seratrodast increased the levels of expression of inducible nitric oxide synthase (iNOS) protein and mRNA in a dose-dependent manner, whereas U-46619 decreased them. We speculated that VSMCs produced TXA2, thereby decreasing nitric oxide production; therefore we measured the accumulation of TXB2 using an enzyme immunoassay. Untreated VSMCs produced about 20 pg/mg protein of TXB2. This was increased by the addition of IL-1beta, to 152.1 +/- 43.0 pg/mg protein after a 24 h incubation; the expression of cyclooxygenase-2 (COX-2) protein was also increased, but there was no effect on the expression of COX-1 and TXA2 synthase. U-63557A, a TXA2 synthase inhibitor, increased the accumulation of nitrite to 1.3-fold that in its absence. CONCLUSIONS: These data suggest that the expression of iNOS and the production of nitric oxide are regulated by the TXA2/PGH2 receptor in IL-1beta-stimulated VSMCs. The endogenous production of TXA2 by the induction of COX-2 from IL-1beta-stimulated VSMCs probably downregulated the production of nitric oxide in VSMCs. TXA2/PGH2 receptor inhibitors may contribute to the reduction in formation of atherosclerosis in lesions with vascular injury by enhancing the production of nitric oxide by VSMCs.
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