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The sphingosine kinase inhibitor N, N-dimethylsphingosine inhibits neointimal hyperplasia

McDonald, Robert A. and Pyne, S. and Pyne, N.J. and Wainwright, C.L. and Wadsworth, R.M. (2010) The sphingosine kinase inhibitor N, N-dimethylsphingosine inhibits neointimal hyperplasia. British Journal of Pharmacology, 159 (3). pp. 543-553. ISSN 1476-5381

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Abstract

Sphingosine-1-phosphate and its receptors may be involved in vascular smooth muscle cell (VSMC) proliferation following vascular injury. Here, we evaluate the effect of d-erythro-N,N-dimethylsphingosine (DMS), a sphingosine kinase (SK) inhibitor, on VSMC proliferation, apoptosis and neointimal formation. Growth responses in vitro to fetal calf serum (FCS) were measured by [3H]-thymidine incorporation and extracellular signal-regulated kinase-1/2 (ERK-1/2) activation in quiescent primary cultures of porcine VSMC in the presence and absence of various concentrations of the SK inhibitor DMS. In vivo treatment with DMS was delivered with a local endoluminal catheter, following balloon injury of coronary arteries. The artery intimal formation was investigated by angiography, myography and histomorphometry. In vitro experiments indicated that DMS induced a dose-dependent reduction in [3H]-thymidine incorporation and ERK-1/2 activation via a protein kinase C (PKC) independent mechanism with an IC50 value of 12 ± 6 and 15 ± 10 µM respectively. DMS also reduced Akt signalling. Four weeks following in vivo delivery of DMS, complete functional endothelial regeneration was observed in all treatment groups, with significant reduction of intimal formation (vehicle 23.7 ± 4.6% vs. DMS infusion 8.92 ± 2.9%, P < 0.05). Taken together, these results demonstrate that local administration of the SK inhibitor, DMS, reduced neointimal formation, and this effect could involve inhibition of ERK-1/2 and Akt signalling, and modulation of smooth muscle growth.