Silencing of Sphingosine kinase 1 Affects Maturation Pathways in Mouse Neonatal Cardiomyocytes

Int J Mol Sci. 2021 Mar 31;22(7):3616. doi: 10.3390/ijms22073616.

Abstract

Sphingosine kinase-1 (Sphk1) and its product, sphingosine-1-phosphate (S1P) are important regulators of cardiac growth and function. Numerous studies have reported that Sphk1/S1P signaling is essential for embryonic cardiac development and promotes pathological cardiac hypertrophy in adulthood. However, no studies have addressed the role of Sphk1 in postnatal cardiomyocyte (CM) development so far. The present study aimed to assess the molecular mechanism(s) by which Sphk1 silencing might influence CMs development and hypertrophy in vitro. Neonatal mouse CMs were transfected with siRNA against Sphk1 or negative control, and subsequently treated with 1 µM angiotensin II (AngII) or a control buffer for 24 h. The results of RNASeq analysis revealed that diminished expression of Sphk1 significantly accelerated neonatal CM maturation by inhibiting cell proliferation and inducing developmental pathways in the stress (AngII-induced) conditions. Importantly, similar effects were observed in the control conditions. Enhanced maturation of Sphk1-lacking CMs was further confirmed by the upregulation of the physiological hypertrophy-related signaling pathway involving Akt and downstream glycogen synthase kinase 3 beta (Gsk3β) downregulation. In summary, we demonstrated that the Sphk1 silencing in neonatal mouse CMs facilitated their postnatal maturation in both physiological and stress conditions.

Keywords: cardiomyocyte; cardiomyocyte hypertrophy; cardiomyocyte maturation; cardiomyocyte proliferation; sphingosine kinase-1; sphingosine-1-phosphate.

MeSH terms

  • Animals
  • Animals, Newborn / metabolism
  • Cell Differentiation / physiology
  • Cell Proliferation / drug effects
  • Lysophospholipids / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / physiology
  • Phosphotransferases (Alcohol Group Acceptor) / genetics*
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • RNA, Small Interfering / pharmacology
  • Receptors, Lysosphingolipid / metabolism
  • Signal Transduction / drug effects
  • Sphingosine / analogs & derivatives
  • Sphingosine / metabolism

Substances

  • Lysophospholipids
  • RNA, Small Interfering
  • Receptors, Lysosphingolipid
  • sphingosine 1-phosphate
  • Phosphotransferases (Alcohol Group Acceptor)
  • Sphk1 protein, mouse
  • sphingosine kinase
  • Sphingosine