Sphingolipid therapy in myocardial ischemia-reperfusion injury
Sphingolipid therapy in myocardial ischemia-reperfusion injury
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DOI：
10.1016/j.bbagen.2007.08.014
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发表时间：
2008-03-01
影响因子：
3
通讯作者：
Lefer, David J.
中科院分区：
文献类型：
--
作者：
Gundewar, Susheel;Lefer, David J.
已知鞘脂在细胞生长、细胞分化和关键信号转导途径中发挥重要的生理作用。近年来的研究表明，鞘脂及其代谢产物在心肌缺血再灌注损伤的发病机制中起着重要作用。我们的实验室研究了N，N，N-三甲基鞘氨醇氯化物（TMS），一种稳定的N-甲基化合成鞘脂类似物对心肌和肝脏缺血-再灌注损伤的细胞保护作用，在临床相关的在体小鼠模型的缺血-再灌注损伤。在缺血发作时静脉注射TMS可减少野生型和肥胖（ob/ob）小鼠的心肌梗死面积。心肌I/R后，野生型小鼠的心脏功能有所改善。此外，TMS还降低了野生型小鼠肝脏I/R后的血清肝酶。对肝脏I/R后的ob/ob小鼠或心肌和肝脏I/R后的db/db小鼠没有细胞保护作用。我们的数据表明，虽然TMS在正常动物I/R后具有细胞保护作用，但TMS的细胞保护作用在肥胖和糖尿病动物中很大程度上减弱，这可能是由于这些动物模型中信号传导机制的改变。本文就TMS等鞘脂在心肌缺血再灌注损伤中的治疗作用及其可能的心肌保护机制作一综述。(C)2007 Elsevier B. V.保留所有权利。
Sphingolipids are known to play a significant physiological role in cell growth, cell differentiation, and critical signal transduction pathways. Recent studies have demonstrated a significant role of sphingolipids and their metabolites in the pathogenesis of myocardial ischemia-reperfusion injury. Our laboratory has investigated the cytoprotective effects of N,N,N-trimethylsphingosine chloride (TMS), a stable N-methylated synthetic sphingolipid analogue on myocardial and hepatic ischemia-reperfasion injury in clinically relevant in vivo murine models of ischemia-reperfusion injury. TMS administered intravenously at the onset of ischemia reduced myocardial infarct size in the wild-type and obese (ob/ob) mice. Following myocardial I/R, there was an improvement in cardiac function in the wild-type mice. Additionally, TMS also decreased serum liver enzymes following hepatic I/R in wild-type mice. The cytoprotective effects did not extend to the ob/ob mice following hepatic I/R or to the db/db mice following both myocardial and hepatic I/R. Our data suggest that although TMS is cytoprotective following I/R in normal animals, the cytoprotective actions of TMS are largely attenuated in obese and diabetic animals which may be due to altered signaling mechanisms in these animal models. Here we review the therapeutic role of TMS and other sphingolipids in the pathogenesis of myocardial ischemia-reperfusion injury and their possible mechanisms of cardioprotection.(C) 2007 Elsevier B.V. All rights reserved.