Role of sphingosine kinase activity in protection of heart against ischemia reperfusion injury.
Role of sphingosine kinase activity in protection of heart against ischemia reperfusion injury.
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发表时间：
2006-10
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通讯作者：
D. Vessey;M. Kelley;Luyi Li;Yong Huang;Hui-zhong Zhou;B. Zhu;J. Karliner
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作者：
D. Vessey;M. Kelley;Luyi Li;Yong Huang;Hui-zhong Zhou;B. Zhu;J. Karliner
背景鞘氨醇激酶（SKase）与保护心脏免受缺血/再灌注损伤有关。对这一假设作了进一步的研究。材料/方法采用离体Langendorff方法研究了大鼠心肌缺血再灌注后SKase活性和心功能（左室发展压、LVDP和梗死面积）的变化。在初始平衡或预处理后，有45分钟的无血流缺血，然后再灌注45分钟。结果缺血时SKase活性下降61%，再灌注后不能恢复。LVDP在再灌注后也没有恢复，梗死面积为47%。短暂的30分钟缺血与SKase活性的可变恢复相关，SKase活性与LVDP恢复直接相关。预处理的心脏减少了一半的SKase活性在缺血期间的下降，并在再灌注活动恢复正常。LVDP恢复79%，梗死范围小。缺血/再灌注后，预处理心脏的S-1-P水平高于非预处理心脏。SKase活性在预处理心脏缺血过程中的下降不能在体外通过蛋白磷酸酶处理来模仿。试图改变SKase的活性从控制，预处理，缺血，或再灌注心脏与ERK 1/2磷酸化是不成功的。在再灌注时用100 nM S-1-P处理非预处理心脏可改善LVDP的恢复。SKase抑制剂二甲基鞘氨醇阻断预处理心脏的血流动力学恢复。结论：SKase活性在缺血损伤后血流动力学功能的恢复和预处理的心脏保护作用中起作用。
BACKGROUND 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. RESULTS 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. CONCLUSIONS The data support a role for SKase activity in recovery of hemodynamic function after ischemic injury and also in the cardioprotective effect of preconditioning.