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

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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.
Original languageEnglish
Pages (from-to)786-798
Number of pages13
JournalTrends in Molecular Medicine
Volume23
Issue number9
Early online date5 Aug 2017
DOIs
Publication statusPublished - 30 Sep 2017

Keywords

  • endothelium
  • sphingosine 1-phosphate
  • sphingosine 1-phosphate receptors
  • vascular remodeling
  • vascular smooth muscle
  • vasoconstriction

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