Effect of the sphingosine kinase 1 selective inhibitor, PF-543 on arterial and cardiac remodeling in a hypoxic model of pulmonary arterial hypertension

Neil MacRitchie, Giora Volpert, Mohammed Al Washih, David G. Watson, Anthony H. Futerman, Simon Kennedy, Susan Pyne, Nigel J. Pyne

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Abstract

Recent studies have demonstrated that the expression of sphingosine kinase 1, the enzyme that catalyses formation of the bioactive lipid, sphingosine 1-phosphate, is increased in lungs from patients with pulmonary arterial hypertension. In addition, Sk1-/- mice are protected from hypoxic-induced pulmonary arterial hypertension. Therefore, we assessed the effect of the sphingosine kinase 1 selective inhibitor, PF-543 and a sphingosine kinase 1/ceramide synthase inhibitor, RB-005 on pulmonary and cardiac remodeling in a mouse hypoxic model of pulmonary arterial hypertension. Administration of the potent sphingosine kinase 1 inhibitor, PF-543 in a mouse hypoxic model of pulmonary hypertension had no effect on vascular remodeling but reduced right ventricular hypertrophy. The latter was associated with a significant reduction in cardiomyocyte death. The protection involves a reduction in the expression of p53 (that promotes cardiomyocyte death) and an increase in the expression of anti-oxidant nuclear factor (erythroid-derived 2)-like 2 (Nrf-2). In contrast, RB-005 lacked effects on right ventricular hypertrophy, suggesting that SK1 inhibition might be nullified by concurrent inhibition of ceramide synthase. Therefore, our findings with PF-543 suggest an important role for SK1 in the development of hypertrophy in PAH.
Original languageEnglish
Pages (from-to)946-955
Number of pages10
JournalCellular Signalling
Volume28
Issue number8
Early online date6 Apr 2016
DOIs
Publication statusPublished - 31 Aug 2016

Keywords

  • sphingosine kinase
  • ssphingosine 1-phosphate
  • hypoxia
  • pulmonary arterial hypertension
  • hypertrophy
  • vascular remodeling

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