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Mediators of Inflammation
Volume 2014 (2014), Article ID 276457, 17 pages
http://dx.doi.org/10.1155/2014/276457
Research Article

Relationship of MMP-14 and TIMP-3 Expression with Macrophage Activation and Human Atherosclerotic Plaque Vulnerability

1Laboratory of Cardiovascular Pathology, School of Clinical Sciences, Level 7, Bristol Royal Infirmary, Bristol BS2 8HW, UK
2School of Clinical Sciences, University of Bristol, Bristol BS2 8HW, UK
3University Medical Centre, 3584 Utrecht, The Netherlands

Received 31 March 2014; Revised 9 July 2014; Accepted 21 July 2014; Published 24 August 2014

Academic Editor: Beatriz De las Heras

Copyright © 2014 Jason L. Johnson et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Matrix metalloproteinase-14 (MMP-14) promotes vulnerable plaque morphology in mice, whereas tissue inhibitor of metalloproteinases-3 (TIMP-3) overexpression is protective.    rabbit foam cells are more invasive and more prone to apoptosis than    cells. We investigated the implications of these findings for human atherosclerosis. In vitro generated macrophages and foam-cell macrophages, together with atherosclerotic plaques characterised as unstable or stable, were examined for expression of MMP-14, TIMP-3, and inflammatory markers. Proinflammatory stimuli increased MMP-14 and decreased TIMP-3 mRNA and protein expression in human macrophages. However, conversion to foam-cells with oxidized LDL increased MMP-14 and decreased TIMP-3 protein, independently of inflammatory mediators and partly through posttranscriptional mechanisms. Within atherosclerotic plaques, MMP-14 was prominent in foam-cells with either pro- or anti-inflammatory macrophage markers, whereas TIMP-3 was present in less foamy macrophages and colocalised with CD206. MMP-14 positive macrophages were more abundant whereas TIMP-3 positive macrophages were less abundant in plaques histologically designated as rupture prone. We conclude that foam-cells characterised by high MMP-14 and low TIMP-3 expression are prevalent in rupture-prone atherosclerotic plaques, independent of pro- or anti-inflammatory activation. Therefore reducing MMP-14 activity and increasing that of TIMP-3 could be valid therapeutic approaches to reduce plaque rupture and myocardial infarction.