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

MacRitchie, Neil and Volpert, Giora and Al Washih, Mohammed and Watson, David G. and Futerman, Anthony H. and Kennedy, Simon and Pyne, Susan and Pyne, Nigel J. (2016) Effect of the sphingosine kinase 1 selective inhibitor, PF-543 on arterial and cardiac remodeling in a hypoxic model of pulmonary arterial hypertension. Cellular Signalling, 28 (8). pp. 946-955. ISSN 1873-3913 (https://doi.org/10.1016/j.cellsig.2016.03.014)

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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.

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