Center for Perioperative Organ Protection, Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina.
Shock. 2021 Nov 1;56(5):755-761. doi: 10.1097/SHK.0000000000001732.
After cardiac arrest (CA) and resuscitation, the unfolded protein response (UPR) is activated in various organs including the brain. However, the role of the UPR in CA outcome remains largely unknown. One UPR branch involves spliced X-box-binding protein-1 (XBP1s). Notably, XBP1s, a transcriptional factor, can upregulate expression of specific enzymes related to glucose metabolism, and subsequently boost O-linked β-N-acetylglucosamine modification (O-GlcNAcylation). The current study is focused on effects of the XBP1 UPR branch and its downstream O-GlcNAcylation on CA outcome. Using both loss-of-function and gain-of-function mouse genetic tools, we provide the first evidence that activation of the XBP1 UPR branch in the post-CA brain is neuroprotective. Specifically, neuron-specific Xbp1 knockout mice had worse CA outcome, while mice with neuron-specific expression of Xbp1s in the brain had better CA outcome. Since it has been shown that the protective role of the XBP1s signaling pathway under ischemic conditions is mediated by increasing O-GlcNAcylation, we then treated young mice with glucosamine, and found that functional deficits were mitigated on day 3 post CA. Finally, after confirming that glucosamine can boost O-GlcNAcylation in the aged brain, we subjected aged mice to 8 min CA, and then treated them with glucosamine. We found that glucosamine-treated aged mice performed significantly better in behavioral tests. Together, our data indicate that the XBP1s/O-GlcNAc pathway is a promising target for CA therapy.
心脏骤停（CA）和复苏后，未折叠蛋白反应（UPR）在包括大脑在内的各种器官中被激活。然而，UPR 在 CA 结果中的作用在很大程度上尚不清楚。UPR 的一个分支涉及剪接的 X 盒结合蛋白-1（XBP1s）。值得注意的是，XBP1s 作为一种转录因子，可以上调与葡萄糖代谢相关的特定酶的表达，随后促进 O-链接 β-N-乙酰氨基葡萄糖修饰（O-GlcNAcylation）。本研究重点关注 XBP1 UPR 分支及其下游 O-GlcNAcylation 对 CA 结果的影响。使用功能丧失和功能获得的小鼠遗传工具，我们首次提供了证据，证明 CA 后大脑中 XBP1 UPR 分支的激活具有神经保护作用。具体来说，神经元特异性 Xbp1 敲除小鼠的 CA 结果更差，而大脑中神经元特异性表达 Xbp1s 的小鼠的 CA 结果更好。由于已经表明 XBP1s 信号通路在缺血条件下的保护作用是通过增加 O-GlcNAcylation 介导的，因此我们用葡糖胺治疗年轻小鼠，发现 CA 后第 3 天功能缺陷得到缓解。最后，在确认葡糖胺可以增强老年大脑中的 O-GlcNAcylation 后，我们让老年小鼠经历 8 分钟的 CA，然后用葡糖胺治疗它们。我们发现葡糖胺治疗的老年小鼠在行为测试中表现明显更好。总之，我们的数据表明 XBP1s/O-GlcNAc 途径是 CA 治疗的有前途的靶点。
