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Cardiovascular drugs inhibit MMP-9 activity from human THP-1 macrophages
Yves Rival1, Nathalie Benéteau, Violaine Chapuis
1Centre de Recherche Pierre Fabre, Castres Cédex, France. yves.rival@pierre-fabre.com
Abstract:
It is now recognized that atherosclerosis complications are related to the unstable character of the plaque rather than its volume. Vulnerable plaques often contain a large lipid core, a reduced content of smooth muscle cells, and accumulation of inflammatory cells. Colocalization of macrophages and active matrix metalloproteinases (MMPs) is likely relevant for atherosclerotic lesion disruption. Nevertheless, MMP activity and regulation by cardiovascular drugs remains poorly defined. In this study, we evaluated the effects of avasimibe, fluvastatin, and peroxisome proliferator-activated receptor (PPAR) ligands on 92-kDa gelatinase B (MMP-9) secretion by human THP-1 macrophages. THP-1 macrophages were treated with compounds for 48 h, and secreted MMP-9 protein was quantified by immunoassay. Avasimibe, fluvastatin, and PPARalpha agonists (fenofibric acid and Wy-14643) significantly reduced, in a concentration-dependent manner, MMP-9 protein (up to 67 +/- 5% for fenofibric acid). In these assays, the PPARgamma selective agonist rosiglitazone displayed a lower efficacy than other compounds. Enzymatic activity of MMP-9 was also decreased by all cardiovascular drugs tested. MMP-9 protein/activity inhibition by cardiovascular drugs was due, at least in part, to a decrease in MMP-9 mRNA. These results show that THP-1 macrophages could be an useful cellular model to investigate effects of compounds on plaque vulnerability through MMP-9 activity.
Insights
Cardiovascular drugs, including avasimibe, fluvastatin, and PPAR agonists, effectively reduce matrix metalloproteinase-9 (MMP-9) secretion and activity in macrophages. This suggests a potential therapeutic strategy for stabilizing atherosclerotic plaques.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Molecular Biology
Background:
- Atherosclerosis complications are linked to plaque instability, not just plaque volume.
- Vulnerable plaques feature large lipid cores, fewer smooth muscle cells, and inflammatory cell accumulation.
- Matrix metalloproteinases (MMPs), particularly MMP-9, are implicated in atherosclerotic lesion disruption, but their regulation by drugs is unclear.
Purpose of the Study:
- To investigate the effects of avasimibe, fluvastatin, and peroxisome proliferator-activated receptor (PPAR) ligands on MMP-9 secretion.
- To assess the impact of these compounds on MMP-9 enzymatic activity.
- To determine if THP-1 macrophages serve as a viable model for studying drug effects on plaque vulnerability via MMP-9.
Main Methods:
- Human THP-1 macrophages were treated with avasimibe, fluvastatin, and various PPAR ligands for 48 hours.
- Secreted MMP-9 protein levels were quantified using immunoassay.
- MMP-9 enzymatic activity and mRNA levels were also assessed.
Main Results:
- Avasimibe, fluvastatin, and PPARalpha agonists (fenofibric acid, Wy-14643) significantly reduced MMP-9 protein secretion in a dose-dependent manner (up to 67% reduction with fenofibric acid).
- PPARgamma agonist rosiglitazone showed lower efficacy compared to other tested compounds.
- All tested cardiovascular drugs decreased MMP-9 enzymatic activity, partly due to reduced MMP-9 mRNA levels.
Conclusions:
- Cardiovascular drugs, including avasimibe, fluvastatin, and PPAR agonists, can inhibit MMP-9 secretion and activity in macrophages.
- The observed reduction in MMP-9 is, in part, mediated by decreased MMP-9 mRNA expression.
- THP-1 macrophages represent a useful cellular model for evaluating drug-induced modulation of plaque vulnerability through MMP-9 activity.
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