Inhibition of neointima hyperplasia of mouse vein grafts by locally applied suramin.

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. METHODS AND 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.