MG53 participates in ischaemic postconditioning through the RISK signalling pathway
MG53 participates in ischaemic postconditioning through the RISK signalling pathway
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MG53通过RISK信号通路参与缺血后处理
DOI：
10.1093/cvr/cvr029
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发表时间：
2011-07-01
影响因子：
10.8
通讯作者：
Xiao, Rui-Ping
中科院分区：
文献类型：
--
作者：
Zhang, Yan;Lv, Fengxiang;Xiao, Rui-Ping
目的近年来的研究表明，缺血后处理(PostC)与已有的缺血预适应(IPC)相似，对缺血/再灌注(IR)损伤具有心脏保护作用，IPC和PostC均可激活再灌注损伤挽救激酶(Risk)通路和存活者激活因子增强(SAFE)通路。PostC在临床上更具吸引力，因为它在可预测的再灌注开始时应用于治疗。我们之前的研究已经证明，MG53是IPC机制的主要组成部分。在此，我们研究了MG53在PostC介导的心肌保护中的潜在作用，并探讨了其可能的机制。方法与结果：我们利用朗宁多夫灌流，研究了野生型(Wt)和MG53(-/-)缺陷(MG53(-/-))小鼠心脏在有或没有PostC的情况下的IR损伤。与wt对照组相比，MG53(-/-)组IR诱导的心肌损伤明显加重。PostC保护WT心脏免受IR引起的心肌梗死、心肌细胞坏死和细胞凋亡的影响，但不能保护MG53(-/-)心脏。MG53(-/-)心脏中PostC保护作用的丧失归因于选择性受损的PostC激活的风险信号。从机制上讲，MG53是小窝蛋白3(CaV3)与磷脂酰肌醇3-激酶(P85-PI3K)的P85亚单位相互作用和PostC介导的风险通路激活所必需的。重要的是，结构-功能研究表明，MG53的三段基序(TRIM)结构域(aa1-284)与CaV3相互作用，而不与P85-PI3K相互作用；而MG53的spry结构域(aa285-477)与P85-PI3K相互作用，但不与CaV3相互作用，表明MG53分别在其N端和C端与CaV3和P85结合。结论MG53主要通过连接CaV3和PI3K以及随后激活风险通路参与后C介导的心肌保护。
Aims Recent studies show that ischaemic postconditioning (PostC), similar to the well-established ischaemic preconditioning (IPC), confers cardioprotection against ischaemia/reperfusion (IR) injury, and both IPC and PostC can activate the reperfusion injury salvage kinase (RISK) pathway and the survivor activating factor enhancement (SAFE) pathway. PostC is clinically more attractive because of its therapeutic application at the predictable onset of reperfusion. Our previous studies have demonstrated that MG53 is a primary component of the IPC machinery. Here, we investigated the potential role of MG53 in PostC-mediated myocardial protection and explored the underlying mechanism.Methods and results Using Langendorff perfusion, we investigated IR injury in wild-type (wt) and MG53-deficient (mg53(-/-)) mouse hearts with or without PostC. IR-induced myocardial damage was markedly exacerbated in mg53(-/-) hearts compared with wt controls. PostC protected wt hearts against IR-induced myocardial infarction, myocyte necrosis, and apoptosis, but failed to protect mg53(-/-) hearts. The loss of PostC protection in mg53(-/-) hearts was attributed to selectively impaired PostC-activated RISK signalling. Mechanistically, MG53 is required for the interaction between caveolin 3 (CaV3) and the p85 subunit of phosphoinositide 3-kinase (p85-PI3K) and PostC-mediated activation of the RISK pathway. Importantly, a structure-function study revealed that the MG53 tripartite motif (TRIM) domain (aa1-284) physically interacted with CaV3 but not p85-PI3K, whereas the MG53 SPRY domain (aa285-477) interacted with p85-PI3K but not CaV3, indicating that MG53 binds to CaV3 and p85 at its N- and C-terminus, respectively.Conclusions We conclude that MG53 participates in PostC-mediated cardioprotection largely through tethering CaV3 and PI3K and subsequent activation of the RISK pathway.