Sphingosine kinase1 : a potential therapeutic target in pulmonary arterial hypertension?

Pyne, Nigel J. and Pyne, Susan (2017) Sphingosine kinase1 : a potential therapeutic target in pulmonary arterial hypertension? Trends in Molecular Medicine, 23 (9). pp. 786-798. ISSN 1471-4914

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    Abstract

    Sphingosine kinase1 (SphK1) knockout mice are protected against pulmonary hypertension and expression levels of the enzyme are increased in the lungs of pulmonary arterial hypertensive (PAH) patients. Moreover,sphingosine1-phosphate can promote vascular remodeling/vasoconstriction in rodent and human pulmonary arterial smooth muscle cell models. Therefore, SphK1 might be a novel target for treatment of PAH. However, in our opinion, more refined strategies to target SphK1 are needed because this enzyme is protective against endothelial dysfunction and can become resistant to SphK1 inhibitors in vascular smooth muscle, thereby potentially limiting their effectiveness in PAH. In addition, SphK1 is involved in maladaptive hypertrophy and we propose that heart failure might be an additional direct target for therapeutic intervention with SphK1 inhibitors.