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Published on: May 31, 2016
A role of matrix metalloproteinase-8 in atherosclerosis
Ross C Laxton1, Yanhua Hu, Johan Duchene
1William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, United Kingdom.
Rationale:
Atherosclerotic lesions express matrix metalloproteinase (MMP)8, which possesses proteolytic activity on matrix proteins particularly fibrillar collagens and on nonmatrix proteins such as angiotensin (Ang) I.
Objective:
We studied whether MMP8 plays a role in atherogenesis.
Methods And Results:
In atherosclerosis-prone apolipoprotein E-deficient mice, inactivating MMP8 resulted in a substantial reduction in atherosclerotic lesion formation. Immunohistochemical examinations showed that atherosclerotic lesions in MMP8-deficient mice had significantly fewer macrophages but increased collagen content. In line with results of in vitro assays showing that Ang I cleavage by MMP8 generated Ang II, MMP8 knockout mice had lower Ang II levels and lower blood pressure. In addition, we found that products of Ang I cleavage by MMP8 increased vascular cell adhesion molecule (VCAM)-1 expression and that MMP8-deficient mice had reduced VCAM-1 expression in atherosclerotic lesions. Intravital microscopy analysis showed that leukocyte rolling and adhesion on vascular endothelium was reduced in MMP8 knockout mice. Furthermore, we detected an association between MMP8 gene variation and extent of coronary atherosclerosis in patients with coronary artery disease. A relationship among MMP8 gene variation, plasma VCAM-1 level, and atherosclerosis progression was also observed in a population-based, prospective study.
Conclusions:
These results indicate that MMP8 is an important player in atherosclerosis.
Insights
Matrix metalloproteinase (MMP)8 plays a key role in atherosclerosis development. Inhibiting MMP8 reduces atherosclerotic lesion formation, inflammation, and blood pressure in mice.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Immunology
Background:
- Atherosclerotic lesions contain matrix metalloproteinase (MMP)8.
- MMP8 exhibits proteolytic activity on matrix proteins like fibrillar collagens and nonmatrix proteins such as angiotensin (Ang) I.
Purpose of the Study:
- To investigate the role of MMP8 in the process of atherogenesis.
- To determine if MMP8 contributes to the development and progression of atherosclerosis.
Main Methods:
- Studied atherosclerosis-prone apolipoprotein E-deficient mice with inactivated MMP8.
- Utilized immunohistochemistry, in vitro assays, and intravital microscopy.
- Analyzed MMP8 gene variation in human coronary artery disease patients.
Main Results:
- MMP8 inactivation significantly reduced atherosclerotic lesion formation in mice.
- MMP8 knockout mice showed fewer macrophages, increased collagen, lower Ang II levels, and reduced blood pressure.
- Reduced VCAM-1 expression and leukocyte adhesion were observed in MMP8-deficient mice.
- MMP8 gene variation associated with coronary atherosclerosis extent and progression in human studies.
Conclusions:
- MMP8 is identified as a significant factor in the pathogenesis of atherosclerosis.
- Targeting MMP8 may offer a therapeutic strategy for cardiovascular disease.
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