Published online before print September 10, 2009, doi: 10.1161/CIRCRESAHA.109.200279
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Submitted on May 1, 2009
Revised on September 1, 2009
Accepted on September 2, 2009
A Role of Matrix Metalloproteinase-8 in Atherosclerosis
Ross C. Laxton ;
From the William Harvey Research Institute (R.C.L., J.D., F.Z., K.-Y.L., R.S.S., C.P.H., A.A., S.Y.), Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom; Cardiovascular Division (Y.H., Z.Z., Q. Xiao, Q. Xu), Kings College London British Heart Foundation Centre, United Kingdom; Human Genetics Division (R.C.L., K.S., S.Y.), School of Medicine, University of Southampton, United Kingdom; Department of Neurology (J.W., S.K.), Medical University of Innsbruck, Innsbruck, Austria; Departamento de Bioquímica y Biología Molecular (C.L.-O.), Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, Spain; and Cardiothoracic Unit (I.A.S.), Southampton General Hospital, Southampton, United Kingdom.
* To whom correspondence should be addressed. E-mail: s.ye{at}qmul.ac.uk.
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.
Key words: atherosclerosis • matrix metalloproteinase • gene
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- Matrix Metalloproteinase-8 and the Regulation of Blood Pressure, Vascular Inflammation, and Atherosclerotic Lesion Growth
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Circ. Res. 2009 105: 827-829.[Extract] [Full Text] [PDF]
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