title: Inhibition of neointima hyperplasia of mouse vein grafts by locally applied suramin.
abstract: BACKGROUND
  Saphenous vein grafts are widely used for aortocoronary bypass surgery as treatment for severe atherosclerosis and often are complicated by subsequent occlusion of the graft vessel.
  
  
  RESULTS
  We described a mouse model of venous bypass graft arteriosclerosis that can be effectively retarded by locally applied suramin, a growth factor receptor antagonist. Mouse isogeneic vessels of the vena cava veins pretreated with suramin were grafted end to end into the carotid arteries and enveloped with a mixture of suramin (1 mmol/L) and pluronic-127 gel. In the untreated group, vessel wall thickening was observed as early as 1 week after surgery and progressed to 4-fold and 10-fold the original thickness in grafted veins at 4 and 8 weeks, respectively. Pluronic-127 gel alone did not influence neointima formation. Suramin treatment reduced the neointima hyperplasia 50% to 70% compared with untreated controls. Immunohistochemical studies demonstrated that a significant proliferation of vascular smooth muscle cells (SMCs) constituted neointimal lesions between 4 and 8 weeks. The majority of SMCs expressed platelet-derived growth factor (PDGF) receptors-alpha and -beta, which were significantly reduced by suramin treatment. In vitro studies indicated that suramin completely blocked PDGF receptor activation or phosphorylation stimulated by PDGF-AB, inhibited activation of mitogen-activated protein kinase (ERK) kinases (MEK1/2) and ERK1/2, and abrogated transcription factor AP-1 DNA-binding activity.
  
  
  CONCLUSIONS
  Suramin inhibited SMC migration and proliferation in vivo and in vitro by blocking PDGF-initiated PDGF receptor and MAPK-AP-1 signaling. These findings indicate that locally applied suramin is effective in a mouse model of venous bypass graft arteriosclerosis.
authors.affiliation: Institute for General and Experimental Pathology, University of Innsbruck Medical School, Innsbruck, Austria.
authors.forename: Y
authors.initials: Y
authors.lastname: Hu
authors.forename: Y
authors.initials: Y
authors.lastname: Zou
authors.forename: H
authors.initials: H
authors.lastname: Dietrich
authors.forename: G
authors.initials: G
authors.lastname: Wick
authors.forename: Q
authors.initials: Q
authors.lastname: Xu
mesh_terms: D000818:Animals; D001161:Arteriosclerosis / Q000473:pathology; D002339:Carotid Arteries / Q000601:surgery; D002465:Cell Movement / Q000187:drug effects; D004789:Enzyme Activation; D006965:Hyperplasia; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D048728:MAP Kinase Kinase Kinase 1; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors*; D017479:Receptors, Platelet-Derived Growth Factor / Q000032:analysis / Q000187:drug effects; D013498:Suramin / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D017539:Tunica Intima / Q000473:pathology; D014680:Veins / Q000637:transplantation*; D014684:Venae Cavae / Q000473:pathology / Q000637:transplantation
chemical_list: D010982:Platelet-Derived Growth Factor; D017978:Receptors, Growth Factor; D018808:Transcription Factor AP-1; C095477:platelet-derived growth factor AB; D013498:Suramin; D020794:Receptor Protein-Tyrosine Kinases; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482578:Map3k1 protein, mouse