Cardiovascular effects of sphingosine-1-phosphate and other sphingomyelin metabolites

1 Upon various stimuli, cells metabolize sphingomyelin from the cellular plasma membrane to form sphingosylphosphorylcholine (SPC) or ceramide. The latter can be further metabolized to sphingosine and then sphingosine-1-phosphate (S1P). Apart from local formation, S1P and SPC are major constituents of blood plasma. 2 All four sphingomyelin metabolites (SMM) can act upon intracellular targets, and at least S1P and probably also SPC can additionally act upon G-protein-coupled receptors. While the molecular identity of the SPC receptors remains unclear, several subtypes of S1P receptors have been cloned and their distribution in cardiovascular tissues is described. 3 In the heart SMM can alter intracellular Ca2+ release, particularly via the ryanodine receptor, and conductance of various ion channels in the plasma membrane, particularly I-K(Ach). While the various SMM differ somewhat in their effects, the above alterations of ion homeostasis result in reduced cardiac function in most cases, and ceramide and/or sphingosine may be the mediators of the negative inotropic effects of tumour necrosis factor. 4 In the vasculature, SMM mainly act as acute vasoconstrictors in most vessels, but ceramide can be a vasodilator. SMM-induced vasoconstriction involves mobilization of Ca2+ from intracellular stores, influx of extracellular Ca2+ via L-type channels and activation of a rho-kinase. 5 Extended exposure to SMM, particularly S1P, promotes several stages of the angiogenic process like endothelial cell activation, migration, proliferation, tube formation and vascular maturation. 6 We propose that SMM are an important class of endogenous modulators of cardiovascular function.