Role of reactive oxygen species-MAP kinase signaling and nitric oxide in matrix metalloproteinase-9 induction in vascular smooth muscle cells

Extracellular matrix breakdown is important for vascular smooth muscle cell migration and vascular remodeling, and requires matrix metalloproteinases. MMP-9 is an inducible enzyme, and is increased in atherosclerotic plaques and in balloon-injured arteries. IL-1β is a cytokine increased at the site of vascular injury, and stimulates MMP9 induction. The aim of the present study was to investigate the role of superoxide and extracellular-signal regulated kinase pathway in IL-1β-stimulated MMP-9 induction in vascular smooth muscle cells.; Superoxide generation using xanthine-xanthine oxidase system stimulated ERK-dependent MMP-9 induction. Stimulation of VSM cells with IL-1β resulted in superoxide production, sustained ERK activation, and MMP-9 induction. Overexpression of MnSOD gene and N-acetyl cysteine treatment attenuated IL-1β-stimulated superoxide production. Treatment of cells with NAC or overexpression of MnSOD gene to inhibit superoxide production resulted in inhibition of sustained ERK activation and MMP-9 induction. Inhibition of IL-1β-stimulated sustained ERK activation by a specific inhibitor PD 98059, also inhibited MMP-9 induction. These results suggest that IL-1β-stimulated superoxide production leads to sustained ERK activation, which in turn is required for MMP-9 induction in VSM cells. The present study for the first time suggests a role of superoxide in IL-1β-stimulated sustained ERK activation and MMP-9 induction.; Endothelial dysfunction or injury decreases nitric oxide production in the vessel wall. Superoxide reacts with nitric oxide with a high degree of affinity and is suggested to decrease nitric oxide bioactivity. I have demonstrated that nitric oxide generation by eNOS gene transfer or by pharmacological approaches inhibits VSM cell migration and IL-1β-stimulated MMP-9 induction. Treatment of cells with nitric oxide donor inhibited IL-β-stimulated superoxide production and sustained ERK activation. These results suggest that nitric oxide inhibits IL-1β-stimulated MMP-9 induction by inhibition of superoxide-ERK signaling. Since MMP-9 is involved in VSM cell migration and neointima formation, the present studies suggest possible mechanisms by which nitric oxide regulates these processes.; In conclusion, modulation of inflammatory responses by regulation of reactive oxygen species generation using either pharmacological approaches or gene therapy protocol provide possible therapeutic targets to control the progression of vasoproliferative diseases.