title: 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.
abstract: 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.
authors.affiliation: Department of Pharmacology in Medical College, Soochow University, Suzhou, China.
authors.forename: Yinan
authors.initials: Y
authors.lastname: Hua
authors.forename: Jie
authors.initials: J
authors.lastname: Xue
authors.forename: Fan
authors.initials: F
authors.lastname: Sun
authors.forename: Lujia
authors.initials: L
authors.lastname: Zhu
authors.forename: Meilin
authors.initials: M
authors.lastname: Xie
mesh_terms: 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
chemical_list: 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