MacRitchie Neil, Volpert Giora, Al Washih Mohammed, Watson David G, Futerman Anthony H, Kennedy Simon, Pyne Susan, Pyne Nigel J
Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde, Glasgow G4 0RE, UK.
Department of Biological Chemistry, Weizmann Insitute of Science, Rehovot 76100, Israel.
Cell Signal. 2016 Aug;28(8):946-55. doi: 10.1016/j.cellsig.2016.03.014. Epub 2016 Apr 6.
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.
最近的研究表明，在肺动脉高压患者的肺部，催化生物活性脂质——1-磷酸鞘氨醇形成的酶鞘氨醇激酶1的表达增加。此外，Sk1基因敲除小鼠可免受低氧诱导的肺动脉高压影响。因此，我们评估了鞘氨醇激酶1选择性抑制剂PF-543和鞘氨醇激酶1/神经酰胺合酶抑制剂RB-005对小鼠肺动脉高压低氧模型中肺和心脏重塑的影响。在小鼠肺动脉高压低氧模型中给予强效鞘氨醇激酶1抑制剂PF-543对血管重塑没有影响，但可减轻右心室肥厚。后者与心肌细胞死亡的显著减少有关。这种保护作用涉及促进心肌细胞死亡的p53表达降低以及抗氧化核因子（红细胞衍生2）样2（Nrf-2）表达增加。相比之下，RB-005对右心室肥厚没有影响，这表明鞘氨醇激酶1的抑制作用可能会因同时抑制神经酰胺合酶而失效。因此，我们使用PF-543的研究结果表明鞘氨醇激酶1在肺动脉高压肥大发展中起重要作用。
