Lipoxygenase Products Regulate Nitric Oxide and Inducible Nitric Oxide Synthase Production in Interleukin-1β Stimulated Vascular Smooth Muscle Cells

Abstract

In cultured vascular smooth muscle cells (VSMCs), interleukin-1β (IL-1β) stimulates inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production. IL-1β 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-1β-induced NO production and iNOS expression. Pretreatment with ONO-RS-082, the secretory PLA₂ (sPLA₂) inhibitor, at 1 to 10μmol/l reduced IL-1β-stimulated nitrite production and iNOS expression. Nordihydroguaiaretic acid (NDGA, 1 to 10μmol/l), the LOX inhibitor, also reduced IL-1β (10 ng/ml)-stimulated nitrite production and iNOS expression in a dose-dependent manner. Exogenous 12(S)-hydroxyeicosatetraenoic acids (HETE) enhanced the IL-1β-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. (Hypertens Res 2003; 26: 177-184)