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

In cultured vascular smooth muscle cells (VSMCs), interieukin-1beta (IL-1beta) stimulates inducible nitric oxide synthase (NOS) expression and nitric oxide (NO) production. IL-1beta also activates phospholipase A(2) (PLA(2)), 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 NOS expression. Pretreatment with ONO-RS-082, the secretory PLA(2) (sPLA(2)) inhibitor, at 1 to 10 mumol/l reduced IL-1beta-stimulated nitrite production and NOS expression. Nordihydroguaiaretic acid (NDGA, 1 to 10 mumnol/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 NOS expression. These results suggest that LOX products play important roles in the regulation of stimulus-induced NO production in VSMCs.