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Updated: Apr 22, 2026
A Human Ex Vivo Atherosclerotic Plaque Model to Study Lesion Biology
Published on: May 6, 2014
Relationship of MMP-14 and TIMP-3 expression with macrophage activation and human atherosclerotic plaque
Jason L Johnson1, Nicholas P Jenkins1, Wei-Chun Huang2
1Laboratory 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.
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.
Insights
Matrix metalloproteinase-14 (MMP-14) promotes plaque vulnerability, while tissue inhibitor of metalloproteinases-3 (TIMP-3) is protective. High MMP-14 and low TIMP-3 in foam cells characterize rupture-prone atherosclerotic plaques, suggesting therapeutic targets.
Area of Science:
- Cardiovascular Biology
- Biochemistry
- Pathology
Background:
- Matrix metalloproteinase-14 (MMP-14) and tissue inhibitor of metalloproteinases-3 (TIMP-3) play roles in atherosclerosis.
- MMP-14 promotes vulnerable plaque morphology, and TIMP-3 overexpression is protective in mouse models.
- Foam cell characteristics differ based on MMP-14 and TIMP-3 expression levels.
Purpose of the Study:
- To investigate the expression and role of MMP-14 and TIMP-3 in human atherosclerotic plaques.
- To determine the relationship between MMP-14, TIMP-3, and plaque stability in humans.
- To explore potential therapeutic strategies targeting MMP-14 and TIMP-3.
Main Methods:
- Human macrophages and foam-cell macrophages were generated in vitro.
- Expression of MMP-14, TIMP-3, and inflammatory markers was analyzed in macrophages and atherosclerotic plaques.
- Plaques were classified as stable or unstable, and rupture-prone based on histological features.
Main Results:
- Proinflammatory stimuli increased MMP-14 and decreased TIMP-3 in human macrophages.
- Oxidized LDL-induced foam cell formation increased MMP-14 and decreased TIMP-3 protein via posttranscriptional mechanisms.
- High MMP-14 and low TIMP-3 expression characterized foam cells in rupture-prone atherosclerotic plaques, irrespective of inflammatory status.
Conclusions:
- Foam cells with high MMP-14 and low TIMP-3 expression are prevalent in rupture-prone human atherosclerotic plaques.
- MMP-14 and TIMP-3 expression in foam cells is largely independent of inflammatory activation.
- Reducing MMP-14 activity and increasing TIMP-3 activity may offer therapeutic benefits for reducing plaque rupture and myocardial infarction.
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