Abstract 13216: Ablation of Matrix Metalloproteinase (MMP)-3 Retards Smooth Muscle Cell Migration and Neointimal Formation: Impact on MMP-9 Activation
Several metalloproteinases (MMPs) can promote vascular smooth muscle cell (VSMC) driven neointima formation, which contributes to restenosis and atherosclerotic fibrous cap formation. Conversely, other actions of MMPs can promote plaque rupture. In recent studies, MMP-3 knockout reduced VSMC accumulation in mouse atherosclerotic plaques, which implies a protective role for MMP-3 in plaque stability. To validate these findings we investigated the effect of MMP-3 knockout on neointima formation after carotid ligation in vivo and VSMC migration after scratch wounding in vitro.28 days after left carotid ligation, MMP-3 knockout significantly reduced neointima formation (75%, p<0.01) compared to wild-type littermates, and also reduced remodelling of ligated and contralateral carotid arteries. Similarly MMP-9-defcient mice also exhibited retarded neointimal formation (83%, p<0.01) whilst MMP-12 ablation had no effect. Co-incubation of recombinant proMMP-3 with active MMP-9 induced MMP-3 activation. Accordingly, gelatin zymography illustrated that MMP-3 knockout abolished MMP-9 activation in ligated carotids and scratch-wounded VSMC cultures. MMP-3 knockout also attenuated VSMC migration into a scratch wound by 59% (p<0.01) compared to WT cells. Addition of exogenous MMP-3 or activated MMP-9 restored migration of MMP-3 knockouts to that of WT VSMC, but exogenous MMP-3 had no effect on migration in MMP-9 knockout VSMC. MMP-9 knockout or knockdown of with siRNA significantly retarded VSMC migration to the same extent as MMP-3 knockout (53% and 75% respectively, both p<0.01). Taken together, these results intimate that MMP-3 and MMP-9 are required and work in concert for efficient VSMC migration and subsequent neointimal formation. Hence, the generation of MMP inhibitors specific for MMP-9 and MMP-3 may be of great therapeutic potential for cardiovascular pathologies.
- © 2010 by American Heart Association, Inc.