title: Cilostazol inhibits matrix invasion and modulates the gene expressions of MMP-9 and TIMP-1 in PMA-differentiated THP-1 cells.
abstract: The invasion of monocytes into the subendothelium space plays an important role in the early stage of atherosclerosis. Cilostazol, a specific phosphodiesterase type III (PDE3) inhibitor, has been shown to exhibit anti-atherosclerotic effect. The present study aimed to investigate the modulating effects of cilostazol on monocyte invasion and the gene expressions of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1. We found that PMA significantly increased the invasive ability and the MMP-9 activity of THP-1 cells, as analyzed by matrix invasion assay and gelatin zymography, respectively. The increased expression of MMP-9 was demonstrated at both the RNA and protein levels by RT/real-time PCR and western blot analysis. These changes were markedly inhibited by cilostazol in a dose-dependent manner, which also could be observed when cAMP analog was used. On the contrary, the expression of TIMP-1, an inhibitor of MMP-9, was significantly upregulated by cilostazol dose dependently at both the RNA and protein levels. Reverse zymography further confirmed the increase of TIMP-1 activity after cilostazol treatment. The increase of TIMP-1 by cilostazol, however, was not cAMP-dependent. Cilostazol reduced the MMP-9 promoter activity and suppressed the nuclear translocation of NF-κB, indicating that the inhibitory effect of cilostazol is at the transcriptional level. In conclusion, the present study provides an additional mechanism underlying the anti-atherosclerotic effect of cilostazol by inhibiting the monocyte invasion and modulating the gene expressions of MMP-9 and TIMP-1 in monocytes upon differentiating to macrophages.
authors.affiliation: Graduate Institute of Clinical Medical Sciences, Chang Gung University, Tao-Yuan, Taiwan, ROC.
authors.forename: Shih-Yi
authors.initials: SY
authors.lastname: Chuang
authors.forename: Su-Hui
authors.initials: SH
authors.lastname: Yang
authors.forename: Tzi-Ya
authors.initials: TY
authors.lastname: Chen
authors.forename: Jong-Hwei S
authors.initials: JH
authors.lastname: Pang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D050197:Atherosclerosis / Q000188:drug therapy / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D000077407:Cilostazol; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005109:Extracellular Matrix / Q000187:drug effects*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*; D017539:Tunica Intima / Q000166:cytology
chemical_list: D004791:Enzyme Inhibitors; D016328:NF-kappa B; D012333:RNA, Messenger; D013777:Tetrazoles; D019715:Tissue Inhibitor of Metalloproteinase-1; D000242:Cyclic AMP; D055372:AMP-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; D000077407:Cilostazol; D013755:Tetradecanoylphorbol Acetate