(Circulation. 1999;100:861-868.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Inhibition of Neointima Hyperplasia of Mouse Vein Grafts by Locally Applied Suramin
From the Institute for General and Experimental Pathology (Y.H., H.D., G.W.), University of Innsbruck Medical School, and the Institute for Biomedical Aging Research (Y.Z., G.W., Q.X.), Austrian Academy of Sciences, Innsbruck, Austria.
Correspondence to Dr Qingbo Xu, Institute for Biomedical Aging Research, Austrian Academy of Sciences, Rennweg 10, A-6020 Innsbruck, Austria. E-mail Qingbo.Xu{at}oeaw.ac.at
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-
and -ß, 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.
Key Words: veins • grafting • arteriosclerosis • receptors • signal transduction
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