title: Relationship of MMP-14 and TIMP-3 expression with macrophage activation and human atherosclerotic plaque vulnerability.
abstract: Matrix metalloproteinase-14 (MMP-14) promotes vulnerable plaque morphology in mice, whereas tissue inhibitor of metalloproteinases-3 (TIMP-3) overexpression is protective. MMP-14(hi) TIMP-3(lo) rabbit foam cells are more invasive and more prone to apoptosis than MMP-14(lo) TIMP-3(hi) 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.
authors.affiliation: Laboratory of Cardiovascular Pathology, School of Clinical Sciences, Level 7, Bristol Royal Infirmary, Bristol BS2 8HW, UK ; School of Clinical Sciences, University of Bristol, Bristol BS2 8HW, UK.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Johnson
authors.affiliation: Laboratory of Cardiovascular Pathology, School of Clinical Sciences, Level 7, Bristol Royal Infirmary, Bristol BS2 8HW, UK ; School of Clinical Sciences, University of Bristol, Bristol BS2 8HW, UK.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Jenkins
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol BS2 8HW, UK.
authors.forename: Wei-Chun
authors.initials: WC
authors.lastname: Huang
authors.affiliation: Laboratory of Cardiovascular Pathology, School of Clinical Sciences, Level 7, Bristol Royal Infirmary, Bristol BS2 8HW, UK ; School of Clinical Sciences, University of Bristol, Bristol BS2 8HW, UK.
authors.forename: Karina
authors.identifier: 0000-0002-4585-7791
authors.initials: K
authors.lastname: Di Gregoli
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol BS2 8HW, UK.
authors.forename: Graciela B
authors.initials: GB
authors.lastname: Sala-Newby
authors.affiliation: University Medical Centre, 3584 Utrecht, The Netherlands.
authors.forename: Vincent P W
authors.initials: VP
authors.lastname: Scholtes
authors.affiliation: University Medical Centre, 3584 Utrecht, The Netherlands.
authors.forename: Frans L
authors.initials: FL
authors.lastname: Moll
authors.affiliation: University Medical Centre, 3584 Utrecht, The Netherlands.
authors.forename: Gerard
authors.initials: G
authors.lastname: Pasterkamp
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol BS2 8HW, UK.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Newby
mesh_terms: D002478:Cells, Cultured; D006801:Humans; D007150:Immunohistochemistry; D008262:Macrophage Activation / Q000502:physiology; D008264:Macrophages / Q000378:metabolism*; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D058226:Plaque, Atherosclerotic / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism*
chemical_list: D019717:Tissue Inhibitor of Metalloproteinase-3; D053511:Matrix Metalloproteinase 14