MMP-7 mediates cleavage of N-cadherin and promotes smooth muscle cell apoptosis

Williams, Helen; Johnson, Jason L.; Jackson, Christopher L.; White, Stephen J.; George, Sarah J.

doi:10.1093/cvr/cvq042

Cited by 91 publications

(63 citation statements)

References 40 publications

(68 reference statements)

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“…21 The latter finding may be because of the ability of MMP-7 to activate smooth muscle cell apoptosis. 27 In the present study, high plasma levels of MMP-7 were associated with more stable atherosclerotic plaques as assessed by their elastin and collagen content, but also with an increased risk for development of coronary events. These observations provide clinical support for an involvement of MMP-7 in atherosclerosis and development of acute cardiovascular events, but the functional role of MMP-7 in plaque destabilization remains to be fully elucidated.…”

Section: Discussionsupporting

confidence: 52%

Elevated Plasma Levels of MMP-12 Are Associated With Atherosclerotic Burden and Symptomatic Cardiovascular Disease in Subjects With Type 2 Diabetes

Gonçalves

Bengtsson

Colhoun³

et al. 2015

ATVB

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Objective— Matrix metalloproteinases (MMPs) degrade extracellular matrix proteins and play important roles in development and tissue repair. They have also been shown to have both protective and pathogenic effects in atherosclerosis, and experimental studies have suggested that MMP-12 contributes to plaque growth and destabilization. The objective of this study was to investigate the associations between circulating MMPs, atherosclerosis burden, and incidence of cardiovascular disease with a particular focus on type 2 diabetes mellitus. Approach and Results— Plasma levels of MMP-1, -3, -7, -10, and -12 were analyzed by the Proximity Extension Assay technology in 1500 subjects participating in the SUMMIT (surrogate markers for micro- and macrovascular hard end points for innovative diabetes tools) study, 384 incident coronary cases, and 409 matched controls in the Malmö Diet and Cancer study and in 205 carotid endarterectomy patients. Plasma MMP-7 and -12 were higher in subjects with type 2 diabetes mellitus, increased with age and impaired renal function, and was independently associated with prevalent cardiovascular disease, atherosclerotic burden (as assessed by carotid intima-media thickness and ankle-brachial pressure index), arterial stiffness, and plaque inflammation. Baseline MMP-7 and -12 levels were increased in Malmö Diet and Cancer subjects who had a coronary event during follow-up. Conclusions— The plasma level of MMP-7 and -12 are elevated in type 2 diabetes mellitus, associated with more severe atherosclerosis and an increased incidence of coronary events. These observations provide clinical support to previous experimental studies, demonstrating a role for these MMPs in plaque development, and suggest that they are potential biomarkers of atherosclerosis burden and cardiovascular disease risk.

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Section: Discussionsupporting

confidence: 52%

Elevated Plasma Levels of MMP-12 Are Associated With Atherosclerotic Burden and Symptomatic Cardiovascular Disease in Subjects With Type 2 Diabetes

Gonçalves

Bengtsson

Colhoun³

et al. 2015

ATVB

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“…Particularly, MMP-7-driven cleavage of N-cadherin-dependent cell-to-cell contacts promotes SMC apoptosis. 8 In addition, the accumulation of ECM cleavage products, such as degraded collagen, induces SMC apoptosis. 9 Collectively, continuous infiltration of inflammatory leukocytes in the fibrous cap mediates SMC apoptosis by cell-to-cell interaction or by protease-mediated alteration of the extracellular environment.…”

Section: Mechanisms Converting a Stable Plaque To A Vulnerable Plaquementioning

confidence: 99%

Atherosclerotic Plaque Destabilization

et al. 2014

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“…We have also recently shown that the frequency of apoptosis is also unaffected by MMP-3 gene deletion. 25 …”

Section: E40 Arterioscler Thromb Vasc Biol September 2011mentioning

confidence: 99%

Matrix Metalloproteinase (MMP)-3 Activates MMP-9 Mediated Vascular Smooth Muscle Cell Migration and Neointima Formation in Mice

Johnson

Dwivedi

Somerville

et al. 2011

ATVB

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125

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Objective-Several matrix metalloproteinases (MMPs) have been implicated in extracellular matrix destruction and other actions that lead to plaque rupture and myocardial infarction. Conversely, other MMPs have been shown to promote vascular smooth muscle cell (VSMC)-driven neointima formation, which contributes to restenosis, fibrous cap formation, and plaque stability. MMP-3 knockout reduced VSMC accumulation in mouse atherosclerotic plaques, implicating MMP-3 in neointima formation. We therefore investigated the effect of MMP-3 knockout on neointima formation after carotid ligation in vivo and VSMC migration in vitro. Methods and Results-Twenty-eight days after left carotid ligation, MMP-3 knockout significantly reduced neointima formation (75%, PϽ0.01) compared with wild-type (WT) littermates, and also reduced remodeling of ligated and contralateral carotid arteries. 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% compared with WT cells. Addition of exogenous MMP-3 or activated MMP-9 restored migration of MMP-3 knockouts to that of WT VSMCs, but exogenous MMP-3 had no effect on migration in MMP-9 knockout VSMCs. MMP-9 knockout or knockdown with small interfering RNA significantly retarded VSMC migration to the same extent as MMP-3 knockout. Conclusion-These results indicate for the first time that MMP-3 mediated activation of MMP-9 is required for efficient neointima formation after carotid ligation in vivo and for VSMC migration in vitro, whereas MMP-12 plays a redundant role. These findings add to the understanding of MMP action in plaque stability and restenosis. and their associated extracellular matrix contributes to occlusive cardiovascular pathologies, including restenosis and atherosclerosis. 1 In the healthy blood vessel, VSMCs reside within the media in a quiescent state. However, after injury, they migrate into the intima, where their growth can result in restriction of normal blood flow. 2 Excessive intimal thickening may compromise lumen patency directly (eg, in the case of restenosis) or accelerate the genesis of superimposed atherosclerosis (eg, in native arteries or vein grafts). 3 On the other hand, VSMC growth within the fibrous cap of an atherosclerotic plaque is considered favorable because it is associated with a stable lesion phenotype, less susceptible to plaque rupture and its deleterious clinical sequelae. 4 The matrix-degrading metalloproteinases (MMPs) are a large family of genetically related enzymes that were defined initially by their ability to degrade many of the extracellular matrix components that are found within healthy and diseased blood vessels. More recently, a variety of nonmatrix substrates, including cytokines and cell surface proteins, have also been identified. 5 As a consequence, 2 major roles in the development of cardiovascular pathologies have been attributed to MMPs: net degradation of the extracellular ma...

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MMP-7 mediates cleavage of N-cadherin and promotes smooth muscle cell apoptosis

Cited by 91 publications

References 40 publications

Elevated Plasma Levels of MMP-12 Are Associated With Atherosclerotic Burden and Symptomatic Cardiovascular Disease in Subjects With Type 2 Diabetes

Elevated Plasma Levels of MMP-12 Are Associated With Atherosclerotic Burden and Symptomatic Cardiovascular Disease in Subjects With Type 2 Diabetes

Atherosclerotic Plaque Destabilization

Matrix Metalloproteinase (MMP)-3 Activates MMP-9 Mediated Vascular Smooth Muscle Cell Migration and Neointima Formation in Mice

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