Mechanism of inhibition of matrix metalloproteinase-9 induction by NO in vascular smooth muscle cells

Vascular smooth muscle (VSM) cell migration is a critical step in the devel opment of a neointima after angioplasty. Matrix metalloproteinases (MMPs) d egrade the basement membrane and extracellular matrix, facilitating VSM cel l migration. Recently, we demonstrated that nitric oxide (NO) inhibits inte rleukin-1 beta (IL-1 beta)-stimulated MMP-9 induction in rat aortic VSM cel ls. In this study, we examined the hypothesis that NO inhibits MMP-9 induct ion by attenuating superoxide generation and extracellular signal-regulated kinase (ERK) activation. Stimulation of VSM cells with IL-1 beta significa ntly (P<0.05) increased superoxide production, ERK activation, and MMP-9 in duction. Pretreatment of VSM cells with the NO donor DETA NONOate significa ntly (P<0.05) decreased IL-1 beta -stimulated superoxide generation. In add ition, pretreatment of VSM cells with a specific ERK pathway inhibitor, PD- 98059, or DETA NONOate inhibited IL-1 beta -stimulated ERK activation and M MP-9 induction. Direct exposure of VSM cells to increased superoxide levels by treatment with xanthine/xanthine oxidase increased ERK activation and M MP-9 induction, whereas pretreatment of cells with PD-98059 significantly ( P<0.05) inhibited xanthine/xanthine oxidase-stimulated ERK activation and M MP-9 induction. We conclude that NO inhibits IL-1<beta>-stimulated MMP-9 in duction by inhibiting superoxide generation and subsequent ERK activation.