Cardiovascular drugs inhibit MMP-9 activity from human THP-1 macrophages.
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.
Rival
Yves
Y
Centre de Recherche Pierre Fabre, Castres Cédex, France. yves.rival@pierre-fabre.com
Benéteau
Nathalie
N
Chapuis
Violaine
V
Taillandier
Thierry
T
Lestienne
Fabrice
F
Dupont-Passelaigue
Elisabeth
E
Patoiseau
Jean-François
JF
Colpaert
Francis C
FC
Junquéro
Didier
D
D000081:Acetamides; D000085:Acetates / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D002317:Cardiovascular Agents / Q000494:pharmacology*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D011345:Fenofibrate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077340:Fluvastatin; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008798:Mevalonic Acid / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077154:Rosiglitazone; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors; D013449:Sulfonamides; D013451:Sulfonic Acids / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors / Q000819:agonists / Q000037:antagonists & inhibitors
C457499:2-chloro-5-nitrobenzanilide; D000081:Acetamides; D000085:Acetates; D000813:Anilides; D002317:Cardiovascular Agents; D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D008077:Lipoproteins, LDL; D061965:Matrix Metalloproteinase Inhibitors; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; D013451:Sulfonic Acids; D045162:Thiazolidinediones; D019715:Tissue Inhibitor of Metalloproteinase-1; D014157:Transcription Factors; C032629:acetyl-LDL; D000077154:Rosiglitazone; C423185:avasimibe; D000077340:Fluvastatin; C006253:pirinixic acid; C006012:fenofibric acid; D002785:Sterol O-Acyltransferase; D020780:Matrix Metalloproteinase 9; D013755:Tetradecanoylphorbol Acetate; D008798:Mevalonic Acid; D011345:Fenofibrate