SAFE通路与鞘脂途径的相互作用在心脏保护中的作用

Interplay between the SAFE and the sphingolipid pathway for cardioprotection

LIFE SCIENCES

影响因子:5.1

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

DOI: 10.1016/j.lfs.2024.123145

摘要

生存激活因子增强（SAFE）通路（包括肿瘤坏死因子α（TNF-α）和信号转导及转录激活因子3（STAT-3））以及鞘脂信号通路（包括鞘氨醇激酶-1（SK1）和鞘磷脂-1（S1P））的激活在促进心肌保护抵抗缺血再灌注损伤（IRI）中起关键作用。我们研究了外源性S1P通过激活SAFE通路是否依赖于SK1的激活以实现心脏保护。在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）同窝鼠中，暴露于模拟缺血条件下，加入SAFE通路激活剂（S1P）和SK1抑制剂（SK1-I）。类似地，来自成年TNF-α KO、STAT-3 KO和WT小鼠的隔离灌流心脏也接受IRI处理，加入S1P和/或SK1-I。评估细胞存活率、梗死面积（IS）及SK1活性。在模拟缺血/IRI条件下，S1P预处理在WT小鼠中降低了细胞死亡，该效果在SK1-I存在时被消除。在TNF-α KO和STAT-3 KO小鼠的细胞和心脏中，S1P未能降低细胞死亡，表明其作用依赖于这些信号通路。S1P预处理在WT和STAT-3 KO小鼠中均增加了SK1活性，但在TNF-α KO小鼠中未见变化。我们的数据强烈提示SK1是通过TNF-α下游激活STAT-3的关键组分，为发展靶向SK1以调控SAFE通路、增强细胞存活的新型心肌保护策略提供理论基础。

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.