Lipoxygenase products regulate nitric oxide and inducible nitric oxide synthase production in interleukin-1beta stimulated vascular smooth muscle cells

Abstract

In cultured vascular smooth muscle cells (VSMCs), interleukin-1beta (IL-1beta) stimulates inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production. IL-1beta also activates phospholipase A2 (PLA2), and induces lipoxygenase (LOX) and cyclooxygenase-2 (COX-2). The present study investigated whether these metabolites are involved in the regulation of IL-1beta-induced NO production and iNOS expression. Pretreatment with ONO-RS-082, the secretory PLA2 (sPLA2) inhibitor, at 1 to 10 micromol/l reduced IL-1beta-stimulated nitrite production and iNOS expression. Nordihydroguaiaretic acid (NDGA, 1 to 10 micromol/l), the LOX inhibitor, also reduced IL-1beta (10 ng/ml)-stimulated nitrite production and iNOS expression in a dose-dependent manner. Exogenous 12(S)-hydroxyeicosatetraenoic acids (HETE) enhanced the IL-1beta-stimulated nitrite production and iNOS expression. On the other hand, the COX inhibitors, indomethacin and NS-398, had little effect on nitrite production or iNOS expression. These results suggest that LOX products play important roles in the regulation of stimulus-induced NO production in VSMCs.