激活幸存者激活因子增强 (SAFE) 途径（包括肿瘤坏死因子-α (TNF-α) 和信号转导器和转录激活剂 - 3 (STAT-3)）和鞘脂信号传导途径（包括鞘氨醇激酶 - 1） (SK1) 和 1-磷酸鞘氨醇 (S1P)) 在促进心脏保护免受缺血再灌注损伤 (IRI) 方面发挥着关键作用。我们研究了外源性 S1P 激活 SAFE 通路是否依赖于 SK1 的激活来保护心脏。从 TNF-α 敲除 (KO) 小鼠、心肌细胞特异性 STAT-3 KO 小鼠及其野生型 (WT) 中分离出心肌细胞在 SAFE 通路 (S1P) 和 SK1 抑制剂 (SK1-I) 触发因素存在的情况下，同窝仔鼠暴露于模拟缺血环境。类似地，对来自成年 TNF-α KO、STAT-3 KO 和 WT 小鼠的分离灌注心脏进行 S1P 和/或 SK1-I 的 IRI。评估了细胞活力、梗死面积 (IS) 和 SK1 活性。 在离体心肌细胞和经受模拟缺血/IRI 的离体心脏中，S1P 预处理减少了 WT 小鼠的细胞死亡，这种作用在 SK1-I 存在时被消除。在从 TNF-α KO 和 STAT-3 KO 小鼠中分离的心肌细胞或心脏中，S1P 未能减少模拟缺血/IRI 后的细胞死亡。有趣的是，S1P预处理增加了WT和STAT-3 KO小鼠中的SK1活性，而TNF-α KO小鼠中没有变化。我们的数据强烈表明SK1是激活SAFE途径中TNF-α下游STAT-3的关键成分，为开发新型心脏保护策略铺平了道路，这些策略可能以 SK1 为靶点来调节 SAFE 途径并增加 IRI 后的细胞存活率。版权所有 © 2024。由 Elsevier Inc. 出版。

Activation of both the Survivor Activating Factor Enhancement (SAFE) pathway (including Tumor Necrosis Factor-alpha (TNF-α) and Signal Transducer and Activator of Transcription-3 (STAT-3)) and the sphingolipid signalling pathway (including sphingosine kinase-1 (SK1) and sphingosine-1 phosphate (S1P)) play a key role in promoting cardioprotection against ischemia-reperfusion injury (IRI). We investigated whether the activation of the SAFE pathway by exogenous S1P is dependent on the activation of SK1 for cardioprotection.Isolated cardiomyocytes from TNF-α knockout (KO) mice, cardiomyocyte-specific STAT-3 KO mice and their wild-type (WT) littermates were exposed to simulated ischemia in the presence of a trigger of the SAFE pathway (S1P) and SK1 inhibitor (SK1-I). Similarly, isolated perfused hearts from adult TNF-α KO, STAT-3 KO and WT mice were subjected to IRI with S1P and/or SK1-I. Cell viability, infarct size (IS) and SK1 activity were assessed.In isolated cardiomyocytes and in isolated hearts subjected to simulated ischemia/IRI, S1P pretreatment decreased cell death in WT mice, an effect that was abrogated in the presence of SK1-I. S1P failed to reduce cell death after simulated ischemia/IRI in both cardiomyocytes or hearts isolated from TNF-α KO and STAT-3 KO mice. Interestingly, S1P pretreatment increased SK1 activity in WT and STAT-3 KO mice, with no changes in TNF-α KO mice.Our data strongly suggest SK1 as a key component to activate STAT-3 downstream of TNF-α in the SAFE pathway, paving the way for the development of novel cardioprotective strategies that may target SK1 to modulate the SAFE pathway and increase cell survival following IRI.Copyright © 2024. Published by Elsevier Inc.