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Membrane type 1 matrix metalloproteinase expression in human atherosclerotic plaques: evidence for activation by
T B Rajavashisth1, X P Xu, S Jovinge
1Atherosclerosis Research Center, Burns and Allen Research Institute, Division of Cardiology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA. rajavashisth@cshs.org
Background:
Matrix metalloproteinases (MMPs) are expressed in atherosclerotic plaques, where in their active form, they may contribute to vascular remodeling and plaque disruption. In this study, we tested the hypothesis that membrane type 1 MMP (MT1-MMP), a novel transmembrane MMP that activates pro-MMP-2 (gelatinase A), is expressed in human atherosclerotic plaques and that its expression is regulated by proinflammatory molecules.
Methods And Results:
MT1-MMP expression was examined in normal and atherosclerotic human arteries by immunocytochemistry with specific antibodies. MT1-MMP expression in human saphenous vein-derived smooth muscle cells (SMCs) maintained in tissue culture was determined under basal conditions and in response to proinflammatory molecules (interleukin [IL]-1alpha, tumor necrosis factor [TNF]-alpha, and oxidized LDL [ox-LDL]) by use of Northern blot and ribonuclease protection assays for mRNA, Western blot and immunoprecipitation for protein, and gelatin zymography for catalytic activity. Medial SMCs of normal vessel wall expressed MT1-MMP. In atherosclerotic arteries, MT1-MMP expression was noted within the complex atheroma colocalizing with SMCs and macrophages (Mphi). Cultured SMCs constitutively expressed MT1-MMP mRNA and protein, which increased 2- to 4-fold over control in a time-dependent manner within 4 to 8 hours of exposure to IL-1alpha, TNF-alpha, and ox-LDL (thiobarbituric acid-reactive substances, 13.4 nmol/mg LDL protein), whereas native LDL had no effect. Flow cytometry revealed MT1-MMP expression by human monocyte-derived Mphi, which increased 3.8-fold over baseline within 6 hours after exposure to 10 ng/mL TNF-alpha.
Conclusions:
This study demonstrates that MT1-MMP, an activator of pro-MMP-2, is expressed by SMCs and Mphi in human atherosclerotic plaques. Furthermore, proinflammatory molecules upregulate MT1-MMP expression in vascular SMCs and Mphi. Thus, activation of SMCs and Mphi by proinflammatory molecules may influence extracellular matrix remodeling in atherosclerosis by regulating MT1-MMP expression.
Insights
Matrix metalloproteinase 1 (MT1-MMP) is found in atherosclerotic plaques and is expressed by smooth muscle cells and macrophages. Proinflammatory molecules increase MT1-MMP expression, potentially influencing extracellular matrix remodeling in atherosclerosis.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Biochemistry
Background:
- Matrix metalloproteinases (MMPs) are implicated in atherosclerotic plaque remodeling and disruption.
- Membrane type 1 MMP (MT1-MMP) is a transmembrane MMP that activates pro-MMP-2.
- The role of MT1-MMP in human atherosclerotic plaques and its regulation by inflammatory factors are not fully understood.
Purpose of the Study:
- To investigate the expression of MT1-MMP in human atherosclerotic plaques.
- To determine if proinflammatory molecules regulate MT1-MMP expression in vascular cells.
Main Methods:
- Immunocytochemistry was used to examine MT1-MMP expression in human arteries.
- Northern blot, ribonuclease protection assays, Western blot, immunoprecipitation, and gelatin zymography were employed to assess MT1-MMP mRNA, protein, and activity in cultured smooth muscle cells (SMCs).
- Flow cytometry was used to evaluate MT1-MMP expression in macrophages (Mphi).
Main Results:
- MT1-MMP was expressed in medial SMCs of normal vessels and within atherosclerotic plaques, co-localizing with SMCs and Mphi.
- Cultured SMCs constitutively expressed MT1-MMP, with a 2- to 4-fold increase in mRNA and protein upon exposure to IL-1alpha, TNF-alpha, and oxidized LDL (ox-LDL).
- Human monocyte-derived Mphi showed increased MT1-MMP expression after TNF-alpha stimulation.
Conclusions:
- MT1-MMP is expressed by SMCs and Mphi within human atherosclerotic plaques.
- Proinflammatory molecules significantly upregulate MT1-MMP expression in vascular SMCs and Mphi.
- Regulation of MT1-MMP by inflammatory mediators may play a role in extracellular matrix remodeling during atherosclerosis.
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