Mechanism of inhibition of matrix metalloproteinase-9 induction by NO in vascular
smooth muscle cells.
Gurjar, Milind V., Jason DeLeon, Ram V. Sharma, and Ramesh C. Bhalla.
Department of Anatomy and Cell Biology, The University of Iowa College of
Medicine, Iowa City, Iowa 52242
APStracts 8:0327A, 2001.
Vascular smooth muscle (VSM) cell migration is a critical step in the development of a
neointima after angioplasty. Matrix metalloproteinases (MMPs) degrade the basement
membrane and the extracellular matrix, facilitating VSM cell migration. Recently, we
demonstrated that nitric oxide (NO) inhibits interleukin-1beta (IL-1beta)-stimulated
MMP-9 induction in rat aortic VSM cells. In this study, we examined the hypothesis that
NO inhibits MMP-9 induction by attenuating superoxide generation and extracellular
signal-regulated kinase (ERK) activation. Stimulation of VSM cells with IL-1beta
significantly (P < 0.05) increased superoxide production, ERK activation, and MMP-9
induction. Pretreatment of VSM cells with the NO donor DETA NONOate significantly
(P < 0.05) decreased IL-1beta-stimulated superoxide generation. In addition,
pretreatment of VSM cells with a specific ERK pathway inhibitor, PD 98059 or DETA
NONOate inhibited, IL-1beta-stimulated ERK activation and MMP-9 induction. Direct
exposure of VSM cells to increased superoxide levels by treatment with
xanthine/xanthine oxidase increased ERK activation and MMP-9 induction, whereas
pretreatment of cells with PD 98059 significantly (P < 0.05) inhibited
xanthine/xanthine oxidase-stimulated ERK activation and MMP-9 induction. We
conclude that NO inhibits IL-1beta-stimulated MMP-9 induction by inhibiting superoxide
generation and subsequent ERK activation.«fnc1»1
Received 30 March 2001; accepted in final form 14 June 2001
APS Manuscript Number A0310-1.
Article publication pending J Appl Physiol
ISSN 1080-4757 Copyright 2001 The American Physiological Society.
Published in APStracts on 29 June 2001