Sphingosylphosphorylcholine induces a hypertrophic growth response throughthe mitogen-activated protein kinase signaling cascade in rat neonatal cardiac myocytes

The sphingolipid metabolites, sphingosine (SPH), SPH 1-phosphate (S1P), and sphingosylphosphorylcholine (SPC), can act as intracellular as well as ext racellular signaling molecules, These compounds have been implicated in the regulation of cell growth, differentiation, and programmed cell death in n onmyocytes, but the effects of sphingolipid metabolites in cardiac myocytes are not known. Cultured neonatal rat cardiac myocytes were stimulated with SPH (I to 10 mu mol/L), S1P (1 to 10 mu mol/L), or SPC (0.1 to 10 mu mol/L ) for 24 hours to determine the effects of sphingolipid metabolites on the rates of protein synthesis, and degradation. Stimulation with SPC led to an increase in the total amount of protein, an accelerated rate of total prot ein synthesis, and a decrease in protein degradation in a dose-dependent ma nner. However, SIP had little effect and SPH had no effect on total protein synthesis. In addition, stimulation with SPC led to a 1.4-fold increase in myocardial cell size and enhanced atrial natriuretic factor gene expressio n. Pretreatment of the cardiac myocytes with pertussis toxin or PD98059 att enuated the SPC-induced hypertrophic growth response. Further, stimulation with SPC increased phosphorylation of mitogen-activated protein kinase (MAP K) and stimulated MAPK enzyme activity. Finally, endothelin-l stimulated th e generation of SPC in cardiac myocytes. The observation that SPC induces a hypertrophic growth response in cardiac myocytes suggests that SPC may pla y a critical role in the development of cardiac hypertrophy. The effects of SPC could be mediated, in part, by activation of a G protein-coupled recep tor and a MAPK signaling cascade.