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Published on: September 26, 2018
A selective matrix metalloproteinase-12 inhibitor retards atherosclerotic plaque development in apolipoprotein
Jason L Johnson1, Laurent Devel, Bertrand Czarny
1Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom. jason.l.johnson@bristol.ac.uk
Objective:
Matrix metalloproteinase (MMP)-12 has been implicated in plaque progression and instability and is also amenable to selective inhibition. In this study, we investigated the influence of a greater than 10-fold selective synthetic MMP-12 inhibitor on plaque progression in the apolipoprotein E knockout mouse model of atherosclerosis.
Methods And Results:
A phosphinic peptide (RXP470.1) that is a potent, selective murine MMP-12 inhibitor significantly reduced atherosclerotic plaque cross-sectional area by approximately 50% at 4 different vascular sites in male and female apolipoprotein E knockout mice fed a Western diet. Furthermore, RXP470.1 treatment resulted in less complex plaques with increased smooth muscle cell:macrophage ratio, less macrophage apoptosis, increased cap thickness, smaller necrotic cores, and decreased incidence of calcification. Additional in vitro and in vivo findings indicate that attenuated monocyte/macrophage invasion and reduced macrophage apoptosis probably underlie the beneficial effects observed on atherosclerotic plaque progression with MMP-12 inhibitor treatment.
Conclusions:
Our data demonstrate that a selective MMP-12 inhibitor retards atherosclerosis development and results in a more fibrous plaque phenotype in mice. Our study provides proof of principle to motivate translational work on MMP-12 inhibitor therapy in humans.
Insights
A selective inhibitor of matrix metalloproteinase (MMP)-12 significantly reduced atherosclerotic plaque progression and complexity in mice. This finding supports further research into MMP-12 inhibitor therapy for human atherosclerosis.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Atherosclerosis Research
Background:
- Matrix metalloproteinase (MMP)-12 is linked to the progression and instability of atherosclerotic plaques.
- Selective inhibition of MMP-12 presents a potential therapeutic strategy.
Purpose of the Study:
- To evaluate the impact of a selective MMP-12 inhibitor on plaque progression.
- To assess the effects on plaque characteristics in a mouse model of atherosclerosis.
Main Methods:
- Utilized apolipoprotein E knockout mice fed a Western diet.
- Administered a potent and selective murine MMP-12 inhibitor (RXP470.1).
- Analyzed atherosclerotic plaque area, composition, and stability markers.
Main Results:
- RXP470.1 treatment reduced plaque cross-sectional area by approximately 50% across four vascular sites.
- Plaques exhibited reduced complexity, characterized by an increased smooth muscle cell to macrophage ratio, decreased macrophage apoptosis, thicker fibrous caps, smaller necrotic cores, and less calcification.
- In vitro and in vivo data suggest reduced monocyte/macrophage invasion and apoptosis contribute to the observed benefits.
Conclusions:
- Selective MMP-12 inhibition effectively retards atherosclerosis development in mice.
- MMP-12 inhibition promotes a more stable, fibrous plaque phenotype.
- This study provides proof of principle for developing MMP-12 inhibitor therapies for human atherosclerosis.
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