1. Academic Validation
  2. Effect of the sphingosine kinase 1 selective inhibitor, PF-543 on arterial and cardiac remodelling in a hypoxic model of pulmonary arterial hypertension

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

  • Cell Signal. 2016 Aug;28(8):946-55. doi: 10.1016/j.cellsig.2016.03.014.
Neil MacRitchie 1 Giora Volpert 2 Mohammed Al Washih 1 David G Watson 1 Anthony H Futerman 2 Simon Kennedy 3 Susan Pyne 1 Nigel J Pyne 4
Affiliations

Affiliations

  • 1 Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde, Glasgow G4 0RE, UK.
  • 2 Department of Biological Chemistry, Weizmann Insitute of Science, Rehovot 76100, Israel.
  • 3 Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow, G12 8QQ, UK.
  • 4 Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde, Glasgow G4 0RE, UK. Electronic address: n.j.pyne@strath.ac.uk.
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 remodelling 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 remodelling 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 sphingosine kinase 1 inhibition might be nullified by concurrent inhibition of ceramide synthase. Therefore, our findings with PF-543 suggest an important role for sphingosine kinase 1 in the development of hypertrophy in pulmonary arterial hypertension.

Keywords

Hypertrophy; Hypoxia; Pulmonary arterial hypertension; Sphingosine 1-phosphate; Sphingosine kinase; Vascular remodelling.

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