Excess sarcoplasmic reticulum-mitochondria calcium transport induced by Sphingosine-1-phosphate contributes to cardiomyocyte hypertrophy

Sphingosine-1-phosphate (S1P) has been shown to possess pro-hypertrophic properties in the heart, but the detailed molecular mechanism that underlies the pathological process is rarely explored. In the present study, we aim to explore the role of S1P-mediated intracellular Ca2+ signaling, with a focus on sarcoplasmic reticulum (SR)-mitochondria communication, in cardiomyocyte hypertrophy. Cultured neonatal rat ventricular myocytes (NRVMs) displayed significantly hypertrophic growth after treatment with 1 mu mol/L S1P for 48 h, as indicated by the cell surface area or mRNA expressions of hypertrophic marker genes (ANP, BNP and beta-MHC). Importantly, mitochondrial Ca2+ and reactive oxygen species (ROS) levels were dramatically elevated upon S1P stimulation, and pharmacological blockage of which abolished NRVM hypertrophy. 0.5 Hz electrical pacing induced similar cytosolic Ca2+ kinetics to S1P stimulation, but unaffected the peak of mitochondrial [Ca2+]. With interference of the expression of type 2 inositol 1,4,5-trisphosphate receptors (IP3R2), which are unemployed in electrical paced Ca2+ activity but may be activated by S1P, alteration in mitochondrial Ca2+ as well as the hypertrophic effect in NRVMs under S1P stimulation were attenuated. The hypertrophic effect of S1P can also be abolished by pharmacological block of S1PR1 or Gi signaling. Collectively, our study highlights the mechanistic role of IP3R2-mediated excess SR-mitochondria Ca2+ transport in S1P-induced cardiomyocyte hypertrophy.

Automated summary

This study highlights the mechanistic role of excessive SR-mitochondria Ca2+ transport mediated by IP3R2 in S1P-induced cardiomyocyte hypertrophy, demonstrating that interference with this process can attenuate the hypertrophic effect. Pharmacological blockage of S1PR1 or Gi signaling can also abolish the hypertrophic effect of S1P.