Aspirin inhibits MMP-2 and MMP-9 expressions and activities through upregulation of PPARalpha/gamma and TIMP gene expressions in ox-LDL-stimulated macrophages derived from human monocytes.
Recently, aspirin has been shown to alleviate matrix metalloproteinase (MMP) expression, but the underlying mechanism is still unclear. In this study, the effects of aspirin on oxidative low-density lipoprotein (ox-LDL)-stimulated human monocyte-derived macrophages were examined. Following treatment of cells with aspirin, MMP-2 and MMP-9 expression and release were significantly reduced. Moreover, expression of peroxisome proliferator-activated receptors (PPARs) alpha and gamma was markedly enhanced. The effect of PPAR inhibitors on MMP levels in aspirin-treated cells was examined. RT-PCR and ELISA assays showed that inhibition of MMP-9 levels by aspirin was notably alleviated by PPAR antagonists. Interestingly, expression of nuclear factor (NF)- kappaB was also decreased by aspirin. RT-PCR study also indicated that aspirin could upregulate the expression of tissue inhibitors of metalloproteinases (TIMP)-1 and TIMP-2. In all of these studies, lower dosage (50 or 100 microg/ml) exerted the best effect. These results demonstrate that aspirin could inhibit MMP-2 and MMP-9 expression through upregulation of PPARalpha/gamma expression in ox-LDL-stimulated macrophages, and could potentially inhibit MMP-2 and MMP-9 activity by induction of TIMP-1 and TIMP-2 expression. This finding may demonstrate a novel pharmacological effect of aspirin protecting against atherosclerotic plaque rupture.
Hua
Yinan
Y
Department of Pharmacology in Medical College, Soochow University, Suzhou, China.
Xue
Jie
J
Sun
Fan
F
Zhu
Lujia
L
Xie
Meilin
M
D001241:Aspirin / Q000008:administration & dosage / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008077:Lipoproteins, LDL / Q000187:drug effects* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000187:drug effects / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D047493:PPAR alpha / Q000187:drug effects / Q000378:metabolism; D047495:PPAR gamma / Q000187:drug effects / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000187:drug effects / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D008077:Lipoproteins, LDL; D047493:PPAR alpha; D047495:PPAR gamma; D010975:Platelet Aggregation Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; C099252:oxidized low density lipoprotein; D019716:Tissue Inhibitor of Metalloproteinase-2; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D001241:Aspirin