A role of matrix metalloproteinase-8 in atherosclerosis.
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.
Laxton, RC; Hu, Y; Duchene, J; Zhang, F; Zhang, Z; Leung, K-Y; Xiao, Q; Scotland, RS; Hodgkinson, CP; Smith, K; Willeit, J; López-Otín, C; Simpson, IA; Kiechl, S; Ahluwalia, A; Xu, Q; Ye, S
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