title: Cilostazol attenuates MCP-1 and MMP-9 expression in vivo in LPS-administrated balloon-injured rabbit aorta and in vitro in LPS-treated monocytic THP-1 cells.
abstract: Monocyte chemoattractant protein-1 (MCP-1) and matrix metalloproteinase-9 (MMP-9) are involved in vascular inflammation. We tested the hypothesis, and explored the underlining mechanisms that cilostazol, a phosphodiesterase 3 inhibitor with antiplatelet and antithrombotic properties, inhibits lipopolysaccharide (LPS)-induced MCP-1 and MMP-9 expression. In a rabbit aorta balloon-injury model, administration of LPS increased macrophage infiltration and MCP-1 and MMP-9 expression; cilostazol supplementation prevented this phenomenon and reduced intimal hyperplasia. In contrast, the reverse zymography showed that cilostazol did not affect TIMP-1 expression in serum. In monocytic THP-1 cells, cilostazol and N6,O2'-dibutyryl-cAMP (dioctanoyl-cAMP, a cAMP analog) dose-dependently inhibited LPS-induced MCP-1 protein expression and MMP-9 activation, but did not affect the tissue inhibitor of metalloproteinase-1. Quantitative real-time polymerase chain reaction (PCR) showed that cilostazol inhibited MCP-1 and MMP-9 mRNA expression. Cilostazol significantly inhibited LPS-induced activation of p38, JNK, and nuclear factor-kappaB, and the respective inhibitors of p38 and JNK greatly reduced the level of LPS-induced MCP-1 and MMP-9, suggesting the involvement of the p38 and JNK pathways. In conclusion, cilostazol administered with LPS in vivo reduced neointimal hyperplasia and macrophage infiltration in the balloon-injured rabbit aorta; in vitro, cilostazol inhibits LPS-induced MCP-1 and MMP-9 expression. These data suggest that cilostazol may play an important role in preventing endotoxin- and injured-mediated vascular inflammation.
authors.affiliation: Division of Cardiovascular Surgery, Tri-service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Chien-Sung
authors.initials: CS
authors.lastname: Tsai
authors.forename: Feng-Yen
authors.initials: FY
authors.lastname: Lin
authors.forename: Yung-Hsiang
authors.initials: YH
authors.lastname: Chen
authors.forename: Tung-Lin
authors.initials: TL
authors.lastname: Yang
authors.forename: Hsiao-Jung
authors.initials: HJ
authors.lastname: Wang
authors.forename: Guo-Shine
authors.initials: GS
authors.lastname: Huang
authors.forename: Chih-Yuan
authors.initials: CY
authors.lastname: Lin
authors.forename: Yi-Tin
authors.initials: YT
authors.lastname: Tsai
authors.forename: Shing-Jong
authors.initials: SJ
authors.lastname: Lin
authors.forename: Chi-Yuan
authors.initials: CY
authors.lastname: Li
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism*; D002404:Catheterization; D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D002633:Chemotaxis / Q000187:drug effects; D000077407:Cilostazol; D000242:Cyclic AMP / Q000096:biosynthesis; D019610:Cytoprotection / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008070:Lipopolysaccharides / Q000008:administration & dosage*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011817:Rabbits; D013777:Tetrazoles / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D008070:Lipopolysaccharides; D016328:NF-kappa B; D013777:Tetrazoles; D018808:Transcription Factor AP-1; D000242:Cyclic AMP; D020928:Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; D000077407:Cilostazol