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Neutral sphingomyelinases mediate the release of ceramide from sphingomyelin in cellular membranes and can be activated by certain stresses. Ceramide can act as a signaling molecule in its own right, or it can be further processed to generate sphingosine (and sphingosine-1-phosphate). GW 4869 is a cell-permeable non-competitive inhibitor of neutral sphingomyelinases (IC50 = 1 μM), but does not affect acid sphingomyelinase activity.1 It inhibits TNF-α-mediated sphingomyelin hydrolysis (100% inhibition at 20 μM) 1 and TNF-α-induced cell death in MCF7 cells without interfering with activation of NF-κB or glutathione depletion in response to TNF.1,2 GW 4869 also reduces the inhibitory effect of oxidized phospholipid products on lipopolysaccharides-mediated induction of interleukin-8 in human aortic endothelial cells 3 and prevents hypoxia-induced pulmonary vasoconstriction in rats in vivo.4
1
Luberto, C., Hassler, D.F., Signorelli, P., et al. Inhibition of tumor necrosis factor-induced cell death in MCF7 by a novel inhibitor of neutral sphingomyelinase. J Biol Chem277(43)41128-41139(2002).
2
Marchesini, N., Luberto, C., and Hannun, Y.A. Biochemical properties of mammalian neutral sphingomyelinase2 and its role in sphingolipid metabolism. J Biol Chem278(16)13775-13783(2003).
3
Walton, K.A., Gugiu, B.G., Thomas, M., et al. A role for neutral sphingomyelinase activation in the inhibition of LPS action by phospholipid oxidation products. J Lipid Res471967-1974(2006).
4
Cogolludo, A., Moreno, L., Frazziano, G., et al. Activation of neutral spingomyelinase is involved in acute hypoxic pulmonary vasoconstriction. Cardiovasc Res82296-302(2009).
Marchesini, N., Luberto, C., and Hannun, Y.A. Biochemical properties of mammalian neutral sphingomyelinase2 and its role in sphingolipid metabolism. J Biol Chem278(16)13775-13783(2003).
Walton, K.A., Gugiu, B.G., Thomas, M., et al. A role for neutral sphingomyelinase activation in the inhibition of LPS action by phospholipid oxidation products. J Lipid Res471967-1974(2006).
Luberto, C., Hassler, D.F., Signorelli, P., et al. Inhibition of tumor necrosis factor-induced cell death in MCF7 by a novel inhibitor of neutral sphingomyelinase. J Biol Chem277(43)41128-41139(2002).
Cogolludo, A., Moreno, L., Frazziano, G., et al. Activation of neutral spingomyelinase is involved in acute hypoxic pulmonary vasoconstriction. Cardiovasc Res82296-302(2009).