TY - JOUR
T1 - Role of sphingosine 1-phosphate in the mitogenesis induced by oxidized low density lipoprotein in smooth muscle cells via activation of sphingomyelinase, ceramidase, and sphingosine kinase
AU - Augé, Nathalie
AU - Nikolova-Karakashian, Mariana
AU - Carpentier, Stéphane
AU - Parthasarathy, Sampath
AU - Nègre-Salvayre, Anne
AU - Salvayre, Robert
AU - Merrill, Alfred H.
AU - Levade, Thierry
PY - 1999/7/30
Y1 - 1999/7/30
N2 - Oxidized LDL (oxLDL) have been implicated in diverse biological events leading to the development of atherosclerotic lesions. We previously demonstrated that the proliferation of cultured vascular smooth muscle cells (SMC) induced by oxLDL is preceded by an increase in neutral sphingomyelinase activity, sphingomyelin turnover to ceramide, and stimulation of mitogen- activated protein kinases (Auge, N., EscargueilBlanc, I., Lajoie-Mazenc, I., Suc, I., Andrieu-Abadie, N., Pieraggi, M. T., Chatelut, M., Thiers, J. C., Jaffrezou, J. P., Laurent, G., Levade, T., Negre-Salvayre, A., and S alvayre, R. (1998) J. Biol. Chem. 273, 12893-12900). Since ceramide can be converted to other bioactive metabolites, such as the well established mitogen sphingosine 1-phosphate (S1P), we investigated whether additional ceramide metabolites are involved in the oxLDLinduced SMC proliferation. We report here that incubation of SMC with oxLDL increased the activities of both acidic and alkaline ceramidases as well as sphingosine kinasem and elevated cellular sphingosine and S1P. Furthermore the mitogenic effect of oxLDL was inhibited by D-erythro-2-(N-myristoylamino)-1-phenyl-1propanol and N,N- dimethylsphingosine which are in- hibitors of ceramidase and sphingosine kinase, respectively. These findings suggest that S1P is a key mediator oltre mitogenic-effect of oxLDL. In agreement with this conclusion, exogenous addition of sphingosine stimulated the proliferation of cultured SMC, and this effect was abrogated by dimethylsphingosine but not by fumonisin B1, an inhibitor of the acylation of sphingosine to ceramide. Exogenous S1P also promoted SMC proliferation. Altogether, these results Strongly suggest that the mitogenic effect of oxLDL in SMC involves the combined activation of sphingomyelinase(s), ceramidase(s), and sphingosine kinase, resulting in the turnover of sphingomyelin to a number of sphingolipid metabolites, of which at least SiP is critical for mitogenesis.
AB - Oxidized LDL (oxLDL) have been implicated in diverse biological events leading to the development of atherosclerotic lesions. We previously demonstrated that the proliferation of cultured vascular smooth muscle cells (SMC) induced by oxLDL is preceded by an increase in neutral sphingomyelinase activity, sphingomyelin turnover to ceramide, and stimulation of mitogen- activated protein kinases (Auge, N., EscargueilBlanc, I., Lajoie-Mazenc, I., Suc, I., Andrieu-Abadie, N., Pieraggi, M. T., Chatelut, M., Thiers, J. C., Jaffrezou, J. P., Laurent, G., Levade, T., Negre-Salvayre, A., and S alvayre, R. (1998) J. Biol. Chem. 273, 12893-12900). Since ceramide can be converted to other bioactive metabolites, such as the well established mitogen sphingosine 1-phosphate (S1P), we investigated whether additional ceramide metabolites are involved in the oxLDLinduced SMC proliferation. We report here that incubation of SMC with oxLDL increased the activities of both acidic and alkaline ceramidases as well as sphingosine kinasem and elevated cellular sphingosine and S1P. Furthermore the mitogenic effect of oxLDL was inhibited by D-erythro-2-(N-myristoylamino)-1-phenyl-1propanol and N,N- dimethylsphingosine which are in- hibitors of ceramidase and sphingosine kinase, respectively. These findings suggest that S1P is a key mediator oltre mitogenic-effect of oxLDL. In agreement with this conclusion, exogenous addition of sphingosine stimulated the proliferation of cultured SMC, and this effect was abrogated by dimethylsphingosine but not by fumonisin B1, an inhibitor of the acylation of sphingosine to ceramide. Exogenous S1P also promoted SMC proliferation. Altogether, these results Strongly suggest that the mitogenic effect of oxLDL in SMC involves the combined activation of sphingomyelinase(s), ceramidase(s), and sphingosine kinase, resulting in the turnover of sphingomyelin to a number of sphingolipid metabolites, of which at least SiP is critical for mitogenesis.
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U2 - 10.1074/jbc.274.31.21533
DO - 10.1074/jbc.274.31.21533
M3 - Article
C2 - 10419457
AN - SCOPUS:0033618381
SN - 0021-9258
VL - 274
SP - 21533
EP - 21538
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 31
ER -