title: Dipyridamole decreases inflammatory metalloproteinase-9 expression and release by human monocytes.
abstract: Matrix metalloproteinase (MMP)-9 plays an important role in stroke by accelerating matrix degradation, disrupting the blood-brain barrier and increasing infarct size. Dipyridamole is an antiplatelet agent with recognised benefits in ischaemic stroke prevention. In addition to its antiplatelet properties, recent studies have reported that dipyridamole also features anti-inflammatory and anti-oxidant properties. We therefore investigated whether dipyridamole can ameliorate the proinflammatory profile of human monocytes, a source of MMP-9 in stroke, in terms of regulation of MMP-9 activity and expression, and explored underlying mechanisms. Human peripheral blood mononuclear cells (PBMC) and U937 cells were treated with increasing concentrations of dipyridamole (up to 10 µg/ml) for 60 minutes before stimulation with tumour necrosis factor (TNF)-α or phorbol myristate acetate (PMA). Exposure of PBMC and U937 to dipyridamole reduced TNF-α- and PMA-induced MMP-9 activity and protein release as well as MMP-9 mRNA, without significantly affecting the release of TIMP-1. This inhibitory effect was independent of dipyridamole-induced cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) increase. Correspondingly, dipyridamole also significantly inhibited TNF-α-induced nuclear factor (NF)-κB activation and nuclear translocation of the p65 NF-κB subunit through a mechanism involving the inhibition of IkBα degradation and p38 MAPK activation. In conclusion, dipyridamole, at therapeutically achievable concentrations, reduces the expression and release of MMP-9 through a mechanism involving p38 MAPK and NF-κB inhibition. These results indicate that dipyridamole exerts anti-inflammatory properties in human monocytes that may favourably contribute to its actions in the secondary prevention of stroke, independent of its antiplatelet properties.
authors.affiliation: C.N.R. Institute of Clinical Physiology, Pisa and Lecce, Italy.
authors.forename: Marika
authors.initials: M
authors.lastname: Massaro
authors.forename: Egeria
authors.initials: E
authors.lastname: Scoditti
authors.forename: Maria Annunziata
authors.initials: MA
authors.lastname: Carluccio
authors.forename: Mariangela
authors.initials: M
authors.lastname: Pellegrino
authors.forename: Nadia
authors.initials: N
authors.lastname: Calabriso
authors.forename: Carlo
authors.initials: C
authors.lastname: Storelli
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Martines
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Caterina
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004176:Dipyridamole / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D000072000:NF-KappaB Inhibitor alpha; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020298:U937 Cells; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; C000606204:NFKBIA protein, human; C498143:RELA protein, human; D012333:RNA, Messenger; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D018808:Transcription Factor AP-1; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D004176:Dipyridamole; D000242:Cyclic AMP; D048051:p38 Mitogen-Activated Protein Kinases; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D006152:Cyclic GMP