安全保护的安全和鞘脂途径之间的相互作用
Interplay between the SAFE and the sphingolipid pathway for cardioprotection
影响因子:5.10000
分区:医学3区 / 药学2区 医学：研究与实验3区
发表日期:2024 Dec 01
作者:
Martin Cour, Sarah Pedretti, Frederic Nduhirabandi, Damian Hacking, Miguel A Frias, Derek J Hausenloy, Sandrine Lecour
摘要
激活幸存者激活因子增强（安全）途径（包括肿瘤坏死因子-Alpha（TNF-α），信号转换器和转录3（Stat-3）（Stat-3））和鞘脂信号传导途径和鞘氨酸激酶-1（SK1）（SK1）和Sphingosine-1 phosti wlay（S1P）的键盘（S1P）的键盘（S1P）缺血再灌注损伤（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）和SK1抑制剂（SK1-I）。同样，将成人TNF-αKO，Stat-3 KO和WT小鼠的孤立灌注心脏与S1P和/或SK1-I一起受到IRI。评估了细胞活力，梗塞大小（IS）和SK1活性。在孤立的心肌细胞和受模拟缺血/IRI的分离心脏中，S1P预处理减少了WT小鼠的细胞死亡，这种作用在SK1-I存在下被废除了。 S1P在模拟从TNF-αKO和STAT-3 KO小鼠中分离出的心肌细胞或心脏中的缺血/IRI后，无法减少细胞死亡。有趣的是，S1P预处理增加了WT和Stat-3 KO小鼠的SK1活性，而TNF-αKO小鼠没有变化。您的数据强烈表明SK1是在安全途径中激活TNF-α下游STAT-3的关键组成部分，从而铺平了针对SAK1的新型Cardioptys straption Sak1的开发方式，从而铺平了SAK1的范围。
Abstract
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.