Ischaemic postconditioning protects against reperfusion injury via the SAFE pathway
Ischaemic postconditioning protects against reperfusion injury via the SAFE pathway
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DOI：
10.1093/cvr/cvp274
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发表时间：
2009-11-01
影响因子：
10.8
通讯作者：
Lecour, Sandrine
中科院分区：
文献类型：
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作者：
Lacerda, Lydia;Somers, Sarin;Lecour, Sandrine
缺血后处理（Ischaemic postconditioning，IPostC）是一种强有力的保护性现象，它通过激活促生存内在信号级联反应来限制再灌注损伤。我们认为，IPostC通过激活新描述的促存活激活因子增强（SAFE）途径，包括激活细胞因子肿瘤坏死因子α，从而发挥其保护梗死的作用。方法和结果从TNF敲除，TNF受体-1敲除，TNF受体-2敲除，心肌细胞特异性STAT-3缺陷小鼠或它们各自的野生型（TNF-WT）或（STAT-3-WT）在再灌注开始时通过缺血发作（IPostC）或用外源性TNF α（0.5 μ g/L）（TNF-PostC）进行后调节。IPostC减少了TNF-WT和TNFR 1（-/-）心脏的梗死面积（IS）（分别减少33%和27%，P < 0.05），而来自TNF-/-或TNFR 2（-/-）的心脏不能进行后处理。TNF-PostC在STAT-3-WT心脏中使IS减少37%（P < 0.05），但未能保护心脏特异性STAT.3（-/-）心脏。在后处理刺激过程中给予渥曼青霉素（PI-3激酶/Akt的抑制剂）或PD 98059（细胞外调节激酶1/2（Erk 1/2）的抑制剂）并不能消除TNF-PostC的梗死保留效应。STAT-3抑制剂AC 490可消除TNF α的保护作用。Western blot分析未显示Akt或Erk 1/2参与TNF-PostC，而STAT-3磷酸化在IPostC和TNF-PostC中均增加。结论SAFE通路的保护作用在IPostC中显示，TNF α，其受体2型和STAT-3的激活。这种信号级联反应的激活独立于众所周知的再灌注损伤补救激酶（RISK）途径，该途径涉及激酶Akt和Erk 1/2。
Aims Ischaemic postconditioning (IPostC) is a powerful protective phenomenon that activates prosurvival intrinsic signalling cascades to limit reperfusion injury. We propose that IPostC confers its infarct-sparing effect via activation of the newly described prosurvival Survivor Activating Factor Enhancement (SAFE) pathway, which involves the activation of the cytokine tumour necrosis factor alpha (TNF alpha) and signal transducer and activator of transcription-3 (STAT-3).Methods and results Isolated ischaemic/reperfused hearts from TNF knockout, TNF receptor-1 knockout, TNF receptor-2 knockout, cardiomyocyte-specific STAT-3-deficient mice or their respective wildtype, (TNF-WT) or (STAT-3-WT), were postconditioned by ischaemic episodes (IPostC) or with exogenous TNF alpha (0.5 mu g/L (TNF-PostC) at the onset of reperfusion. IPostC reduced infarct size (IS) in TNF-WT and TNFR1(-/-) hearts (by 33 and 27%, respectively, P < 0.05), whereas hearts from TNF-/- or TNFR2(-/-) failed to be postconditioned. TNF-PostC reduced IS by 37% (P < 0.05) in STAT-3-WT hearts but failed to protect cardiac-specific STAT.3(-/-) hearts. Administration of wortmannin, an inhibitor of PI-3 kinase/Akt, or PD98059, an inhibitor of extracellular regulated kinase 1/2 (Erk1/2), during the postconditioning stimulus did not abolish the infarct-sparing effect of TNF-PostC. AC490, an inhibitor of STAT-3, abrogated the protective effect of TNF alpha. Western blot analysis did not demonstrate the involvement of Akt or Erk1/2 in TNF-PostC, whereas STAT-3 phosphorylation was increased in both IPostC and TNF-PostC.Conclusion The protective effect of the SAFE pathway is shown in IPostC, with the activation of TNF alpha, its receptor type 2, and STAT-3. This signalling cascade is activated independently of the well-known Reperfusion Injury Salvage Kinases (RISK) pathway, which involves the kinases Akt and Erk1/2.