Sphingosine kinase 1 (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, sphingosine 1-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.

鞘氨醇激酶1（SphK1敲除小鼠可预防肺动脉高压，并且在肺动脉高压（PAH）患者的肺中该酶的表达水平增加。此外，1-磷酸鞘氨醇可促进啮齿动物和人肺动脉平滑肌细胞模型中的血管重塑/血管收缩。因此，SphK1可能是治疗PAH的新型靶标。但是，在我们看来，需要更精确的策略来靶向SphK1，因为该酶具有保护内皮功能的作用，并且可以抵抗血管平滑肌中的SphK1抑制剂，从而潜在地限制了其在PAH中的有效性。此外，SphK1参与了适应不良的肥大，我们认为心力衰竭可能是SphK1抑制剂进行治疗干预的另一个直接靶标。