Interferon-γ mediates the protective effects of soluble receptor for advanced glycation end-product in myocardial ischemia/reperfusion
Interferon-γ mediates the protective effects of soluble receptor for advanced glycation end-product in myocardial ischemia/reperfusion
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干扰素-γ介导可溶性受体对心肌缺血/再灌注晚期糖基化终产物的保护作用
DOI：
10.1038/s41374-018-0102-z
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发表时间：
2019-03-01
影响因子：
5
通讯作者：
Guo, Caixia
中科院分区：
文献类型：
--
作者：
Dang, Mengqiu;Zeng, Xiangjun;Guo, Caixia
泛素蛋白酶体系统（UPS）对于蛋白质降解至关重要，并且在心肌缺血/再灌注（MI/R）损伤中发挥着关键作用。先前的研究表明，晚期糖基化终末产物的可溶性受体 (sRAGE) 通过上调蛋白酶体亚基来抑制 MI/R 诱导的细胞凋亡。然而，其机制仍不清楚。通过结扎小鼠冠状动脉左前降支（LAD）建立 MI/R 模型。在结扎前，将重组sRAGE蛋白或盐水注射到心肌内，同时腹膜内注射或不注射中和干扰素-γ(IFN-γ)抗体。在心肌细胞中，用“缺血缓冲液”模拟缺血，并通过腺病毒过表达sRAGE。表达β 5i 干扰RNA 的腺病毒被用来敲低心肌细胞中的β 5i。 sRAGE 在假手术小鼠和 MI/R 小鼠中均诱导 IFN-γ。使用 IFN-γ 抗体阻断 IFN-γ，消除了 sRAGE 对 MI/R 引起的心功能障碍、梗死面积和细胞凋亡的救援作用。阻断 IFN-γ 可逆转心脏 MI/R 期间 sRAGE 诱导的 β 1i 和 β 5i 表达上调，同时降低胰凝乳蛋白酶样蛋白酶体活性。此外，IFN-γ抗体消除了 sRAGE 对 MI/R 诱导的 p38 和 c-Jun N 末端激酶 (JNK) 激活以及体内和体外 p53 表达的抑制作用。然而，在体外缺氧/复氧 (H/R) 过程中，β 5i 的敲低消除了 sRAGE 的抗凋亡作用，同时 p53 的降解减少。我们的数据表明 sRAGE 预防 MI/R 诱导的心脏细胞凋亡的新机制：sRAGE 通过 β 5i 亚基降解 p53 来抑制 MI/R 诱导的心肌细胞凋亡，而β 5i 亚基通过上调 IFN-γ 增加。
The ubiquitin-proteasome system (UPS) is essential for protein degradation and plays critical roles in myocardial ischemia/reperfusion (MI/R) injuries. Previous studies have demonstrated that the soluble receptor for advanced glycation end-product (sRAGE) inhibited MI/R-induced apoptosis by upregulating proteasome subunits. However, the mechanism remains unknown. An MI/R model was established by left anterior descending (LAD) coronary artery ligation in mice. Recombinant sRAGE protein or saline was injected intramyocardially with or without neutralizing interferon-gamma (IFN-gamma) antibody injected intraperitoneally before ligation. In cardiomyocytes, ischemia was simulated with "ischemia buffer" and sRAGE was overexpressed by adenovirus. Adenovirus expressing the interference RNA of beta 5i was used to knockdown beta 5i in cardiomyocytes. IFN-gamma was induced by sRAGE both in sham and MI/R mice. Blockade of IFN-gamma using IFN-gamma antibody abolished the rescue effects of sRAGE for cardiac dysfunction, infarct size and apoptosis provoked by MI/R. Blockade of IFN-gamma reversed the upregulation of beta 1i and beta 5i expression induced by sRAGE during MI/R in heart, accompanied by decreasing chymotrypsin-like proteasome activity. In addition, IFN-gamma antibody abolished the suppressing effect of sRAGE on MI/R-induced p38 and c-Jun N-terminal kinase (JNK) activation, as well as p53 expression, both in vivo and in vitro. However, knockdown of beta 5i abolished the antiapoptosis effect of sRAGE during hypoxia/reoxygenation (H/R) in vitro, accompanied by decreased degradation of p53. Our data suggest a novel mechanism for sRAGE in preventing MI/R-induced apoptosis in heart: sRAGE inhibits MI/R-induced apoptosis in cardiomyocytes by degrading p53 by beta 5i subunit that is increased via upregulation of IFN-gamma.