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 > School of Cardiovascular & Metabolic Health College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
| 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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