Vessey Donald A, Kelley Michael, Li Luyi, Huang Yong, Zhou Hui-Zhong, Zhu Bo Qing, Karliner Joel S
Liver Study Unit, Department of Veterans Affairs Medical Center San Francisco CA 94121, USA.
Med Sci Monit. 2006 Oct;12(10):BR318-24. Epub 2006 Sep 25.
Sphingosine kinase (SKase) has been implicated in the protection of hearts from ischemia/reperfusion injury. This hypothesis was further examined.
MATERIAL/METHODS: Changes in SKase activity and cardiac function (left ventricular developed pressure, LVDP, and infarct size) in response to ischemia and reperfusion were studied in adult rat hearts by the ex vivo Langendorff method. Following initial equilibration or preconditioning, there was 45 min no-flow ischemia and then 45 min of reperfusion.
SKase activity declined 61% during ischemia and did not recover upon reperfusion. LVDP also did not recover upon reperfusion and the infarct size was 47%. A short 30 min period of ischemia was associated with variable recovery of SKase activity that directly correlated with LVDP recovery. Preconditioning of hearts reduced the decrease in SKase activity during ischemia by half, and upon reperfusion activity returned to normal. The LVDP recovered 79% and infarct size was small. Preconditioned hearts had higher S-1-P levels after ischemia/reperfusion relative to non-preconditioned hearts. The decline in SKase activity during ischemia of preconditioned hearts could not be mimicked in vitro by treatment with protein phosphatases. Attempts to alter activity of SKase from control, preconditioned, ischemic, or reperfused hearts by phosphorylation with ERK1/2 were unsuccessful. Treatment of non-preconditioned hearts at reperfusion with 100 nM S-1-P improved recovery of LVDP. The SKase inhibitor dimethylsphingosine blocked hemodynamic recovery in preconditioned hearts.
The data support a role for SKase activity in recovery of hemodynamic function after ischemic injury and also in the cardioprotective effect of preconditioning.
鞘氨醇激酶（SKase）与心脏免受缺血/再灌注损伤的保护作用有关。本研究对这一假说进行了进一步验证。
材料/方法：采用离体Langendorff方法，研究成年大鼠心脏在缺血和再灌注过程中SKase活性及心脏功能（左心室舒张末压、LVDP和梗死面积）的变化。在初始平衡或预处理后，进行45分钟无血流缺血，然后再灌注45分钟。
缺血期间SKase活性下降61%，再灌注时未恢复。再灌注时LVDP也未恢复，梗死面积为47%。短暂30分钟的缺血与SKase活性的可变恢复有关，这与LVDP的恢复直接相关。心脏预处理使缺血期间SKase活性的下降减少一半，再灌注时活性恢复正常。LVDP恢复了79%，梗死面积较小。预处理的心脏在缺血/再灌注后相对于未预处理的心脏具有更高的S-1-P水平。预处理心脏缺血期间SKase活性的下降在体外不能通过蛋白磷酸酶处理来模拟。用ERK1/2磷酸化来改变对照、预处理、缺血或再灌注心脏中SKase的活性的尝试均未成功。在再灌注时用100 nM S-1-P处理未预处理的心脏可改善LVDP的恢复。SKase抑制剂二甲基鞘氨醇阻断了预处理心脏的血流动力学恢复。
数据支持SKase活性在缺血性损伤后血流动力学功能恢复以及预处理的心脏保护作用中发挥作用。
