title: Interleukin-18/WNT1-inducible signaling pathway protein-1 signaling mediates human saphenous vein smooth muscle cell proliferation.
abstract: We demonstrate for the first time that the pro-inflammatory cytokine interleukin (IL)-18 stimulates rapid and significant proliferation of SMC derived from human saphenous vein (VSMC), but not coronary artery. IL-18 also stimulates VSMC growth. Further investigations revealed that IL-18-induced VSMC proliferation was Wnt inducible secreted protein-1 (WISP1) dependent. In addition to inducing its own expression via phosphatidylinositol 3-kinase/Akt-dependent IKK/NF-κB activation, IL-18 stimulated glycogen synthase kinase 3β phosphorylation and degradation, β-catenin nuclear translocation and stabilization, T-cell factor-lymphoid enhancer binding factor (TCF-LEF) activation, and WISP1 induction. Moreover, WISP1 induced its own expression, and that of survivin and multiple matrix metalloproteinases via β-catenin/TCF-LEF interaction. WISP1 also activated AP-1, but not NF-κB, and induced matrix metalloproteinase (MMP)9 transcription in part via AP-1. Interestingly, WISP1 failed to regulate tissue inhibitors of matrix metalloproteinases (TIMP) expression. These novel findings indicate that IL-18 induces a series of signaling events that result in WISP1-mediated VSMC proliferation, survival and MMP induction that are key components of vein graft stenosis and this may be amplified by IL-18 and WISP1 autoregulation and cross-regulation.
authors.affiliation: Cardiothoracic Surgery, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Venkatapuram Seenu
authors.initials: VS
authors.lastname: Reddy
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Valente
authors.forename: Patrice
authors.initials: P
authors.lastname: Delafontaine
authors.forename: Bysani
authors.initials: B
authors.lastname: Chandrasekar
mesh_terms: D021581:Active Transport, Cell Nucleus; D055511:CCN Intercellular Signaling Proteins; D049109:Cell Proliferation; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D006965:Hyperplasia; D051550:I-kappa B Kinase / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation; D055550:Protein Stability; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012501:Saphenous Vein / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D051176:beta Catenin / Q000378:metabolism
chemical_list: D055511:CCN Intercellular Signaling Proteins; C116396:CCN4 protein, human; C495270:CTNNB1 protein, human; D018836:Inflammation Mediators; D020382:Interleukin-18; D047908:Intracellular Signaling Peptides and Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D018808:Transcription Factor AP-1; D051176:beta Catenin; D058539:Phosphatidylinositol 3-Kinase; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase; D038362:Glycogen Synthase Kinase 3; D020780:Matrix Metalloproteinase 9