D-erythro-N,N-dimethylsphingosine inhibits bFGF-induced proliferation of cerebral, aortic and coronary smooth muscle cells.
The role of sphingosine kinase (SphK) on basic fibroblast growth factor (bFGF)-induced proliferation of cerebral, aortic and coronary smooth muscle cells (SMC) was addressed using D-erythro-N,N-dimethylsphingosine (DMS), an inhibitor of SphK which blocks conversion of sphingosine to sphingosine-1-phosphate (S1P). DMS concentration-dependently reduced the bFGF-induced proliferation of rat cerebral and aortic, and human coronary SMC. This suggests that SphK is one of the key enzymes in the mitogenic response to bFGF in vascular SMC as supported by the finding that S1P stimulated proliferation of SMC. Fumonisin B1, a dihydroceramidesynthase inhibitor which blocks the conversion of dihydrosphingosine to seramide, did not affect SMC proliferation induced by bFGF. Staurosporine, an inhibitor of protein kinase C (PKC), inhibited proliferation of SMC induced by bFGF, and both bFGF- and S1P-induced proliferation of SMC was sensitive to pertussis toxin (PTX), an inhibitor of Gi-protein activity. The present study thus demonstrates that SphK, PKC and Gi-protein activities are required for bFGF-mitogenic signaling in SMC. The bFGF mitogenic effect in vascular SMC might at least in part act via the SphK pathway and a Gi-protein.
Xu
Cang-Bao
CB
Department of Medicine, Lund University, Division of Experimental Vascular Research, S-22185, Lund, Sweden.
Zhang
Yaping
Y
Stenman
Emelie
E
Edvinsson
Lars
L
D000704:Analysis of Variance; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D001921:Brain / Q000166:cytology; D002455:Cell Division / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology; D004789:Enzyme Activation; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D006801:Humans; D008297:Male; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000187:drug effects* / Q000378:metabolism*; D011336:Probability; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D012680:Sensitivity and Specificity; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000099157:Sphingosine Kinase
D016222:Fibroblast Growth Factor 2; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D000099157:Sphingosine Kinase; C061800:N,N-dimethylsphingosine