Remote Ischemic Preconditioning Protects against Liver Ischemia-Reperfusion Injury via Heme Oxygenase-1-Induced Autophagy
Remote Ischemic Preconditioning Protects against Liver Ischemia-Reperfusion Injury via Heme Oxygenase-1-Induced Autophagy
复制标题
远程缺血预处理通过血红素加氧酶 1 诱导的自噬预防肝脏缺血再灌注损伤
DOI：
10.1371/journal.pone.0098834
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发表时间：
2014-06-10
期刊：
影响因子：
3.7
通讯作者：
Li, Xiangcheng
中科院分区：
文献类型：
--
作者：
Wang, Yun;Shen, Jian;Li, Xiangcheng
背景越来越多的证据表明，自噬与预适应在肝脏缺血/再灌注(IR)中的保护作用有关。血红素氧合酶-1(HO-1)在抑制炎症反应和防止IR后的细胞凋亡反应中起重要作用。我们先前已经证明，在远程缺血预适应(RIPC)后，HO-1在移植肝中表达上调。本研究的目的是证实RIPC通过HO-1介导的自噬对IR具有保护作用。方法肝缺血前行肢体局部缺血行RIPC，术前抑制HO-1活性。通过检测轻链3-II(LC3-II)的表达来评价自噬作用。在体外自噬模型和矿物油诱导的IR模型中检测HO-1/细胞外信号相关激酶(ERK)/p38/丝裂原活化蛋白激酶(MAPK)通路。结果肝缺血再灌注后12~24 h，肝细胞中LC3-II的表达达到高峰，超微结构显示肝细胞内有丰富的自噬小体。当HO-1失活时，自噬被抑制，我们认为这导致了体内肝脏IR损伤(IRI)的加重。氯化高铁血红素诱导的自噬也能保护体外培养的大鼠肝细胞免受IRI，这一保护作用可被HO-1 siRNA取消。P38-MAPK和ERK1/2的磷酸化在氯化血红素处理的肝细胞中上调，在HO-1 siRNA处理后下调。结论RIPC可能通过诱导依赖HO-1/p38-MAPK的自噬来保护肝脏免受IRI。
Background Growing evidence has linked autophagy to a protective role of preconditioning in liver ischemia/reperfusion (IR). Heme oxygenase-1 (HO-1) is essential in limiting inflammation and preventing the apoptotic response to IR. We previously demonstrated that HO-1 is up-regulated in liver graft after remote ischemic preconditioning (RIPC). The aim of this study was to confirm that RIPC protects against IR via HO-1-mediated autophagy. Methods RIPC was performed with regional ischemia of limbs before liver ischemia, and HO-1 activity was inhibited pre-operation. Autophagy was assessed by the expression of light chain 3-II (LC3-II). The HO-1/extracellular signal-related kinase (ERK)/p38/mitogen-activated protein kinase (MAPK) pathway was detected in an autophagy model and mineral oil-induced IR in vitro. Results In liver IR, the expression of LC3-II peaked 12–24 h after IR, and the ultrastructure revealed abundant autophagosomes in hepatocytes after IR. Autophagy was inhibited when HO-1 was inactivated, which we believe resulted in the aggravation of liver IR injury (IRI) in vivo. Hemin-induced autophagy also protected rat hepatocytes from IRI in vitro, which was abrogated by HO-1 siRNA. Phosphorylation of p38-MAPK and ERK1/2 was up-regulated in hemin-pretreated liver cells and down-regulated after treatment with HO-1 siRNA. Conclusions RIPC may protect the liver from IRI by induction of HO-1/p38-MAPK-dependent autophagy.