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

MacRitchie, N., Volpert, G., Al Washih, M., Watson, D. G., Futerman, A. H., Kennedy, S. , Pyne, S. and Pyne, N. J. (2016) Effect of the sphingosine kinase 1 selective inhibitor, PF-543 on arterial and cardiac remodelling in a hypoxic model of pulmonary arterial hypertension. Cellular Signalling, 28(8), pp. 946-955. (doi: 10.1016/j.cellsig.2016.03.014) (PMID:27063355) (PMCID:PMC4913619)

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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 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.

Item Type:Articles
Additional Information:This work was support by the British Heart Foundation (PG/12/24/29476) to NJP, SK and SP.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:MacRitchie, Dr Neil and Kennedy, Professor Simon
Authors: MacRitchie, N., Volpert, G., Al Washih, M., Watson, D. G., Futerman, A. H., Kennedy, S., Pyne, S., and Pyne, N. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Cellular Signalling
Publisher:Elsevier
ISSN:0898-6568
ISSN (Online):1873-3913
Published Online:06 April 2016
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Cellular Signalling 28(8):946-955
Publisher Policy:Reproduced under a Creative Commons License

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