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. 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-α and -β, 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.