Critical role of acidic sphingomyelinase in murine hepatic ischemia-reperfusion injury
Critical role of acidic sphingomyelinase in murine hepatic ischemia-reperfusion injury
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DOI：
10.1002/hep.21285
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发表时间：
2006-09-01
期刊：
影响因子：
13.5
通讯作者：
Morales, Albert
中科院分区：
文献类型：
--
作者：
Llacuna, Laura;Marí, Montserrat;Morales, Albert
肝缺血/再灌注损伤的分子机制尚不完全清楚。我们研究了神经酰胺在小鼠热肝I/R损伤模型中的作用。这种鞘脂诱导细胞死亡并参与肿瘤坏死因子（TNF）信号传导。在小鼠缺血肝脏再灌注阶段后，肝脏神经酰胺水平短暂升高，这是由于酸性鞘磷脂酶（ASMase）的早期激活以及随后的酸性神经酰胺酶刺激所致。在体内施用ASMase抑制剂、丙咪嗪或通过siRNA敲低ASMase减少了I/R期间神经酰胺的产生，并减弱了血清ALT水平、肝细胞坏死、细胞色素c释放和半胱天冬酶-3活化。ASMase诱导的神经酰胺生成激活JNK，导致Bim（L）磷酸化和易位到线粒体，因为丙咪嗪抑制ASMase阻止了这些事件。相反，与溶剂处理的小鼠相比，神经酰胺酶抑制剂N-油乙醇胺（NOE）阻断神经酰胺catalysts，增强神经酰胺水平和增强I/R损伤。喷替福林治疗防止TNF上调和ASMase活化。此外，与12只溶剂处理的小鼠中的4只相比，11只丙咪嗪处理的小鼠中的9只在全肝缺血后7天存活，而8只NOE处理的小鼠中的8只在全肝缺血后2天内死亡。总之，从ASMase产生的神经酰胺在I/R诱导的肝损伤中起着关键作用，其调节可能具有治疗意义。
The molecular mechanisms of hepatic ischemia/reperfusion (I/R) damage are incompletely understood. We investigated the role of ceramide in a murine model of warm hepatic I/R injury. This sphingolipid induces cell death and participates in tumor necrosis factor (TNF) signaling. Hepatic ceramide levels transiently increased after the reperfusion phase of the ischemic liver in mice, because of an early activation of acidic sphingomyelinase (ASMase) followed by acid ceramidase stimulation. In vivo administration of an ASMase inhibitor, imipramine, or ASMase knockdown by siRNA decreased ceramide generation during I/R, and attenuated serum ALT levels, hepatocellular necrosis, cytochrome c release, and caspase-3 activation. ASMase-induced ceramide generation activated JNK resulting in Bim(L) phosphorylation and translocation to mitochondria, as the inhibition of ASMase by imipramine prevented these events. In contrast, blockade of ceramide catabolism by N-oleyolethanolamine (NOE), a ceramidase inhibitor, enhanced ceramide levels and potentiated I/R injury compared with vehicle-treated mice. Pentoxifylline treatment prevented TNF upregulation and ASMase activation. Furthermore, 9 of 11 mice treated with imipramine survived 7 days after total liver ischemia, compared with 4 of 12 vehicle-treated mice, whereas 8 of 8 NOE-treated mice died within 2 days of total liver ischemia. In conclusion, ceramide generated from ASMase plays a key role in I/R-induced liver damage, and its modulation may be of therapeutic relevance.