Sirtuin 1 Mediates Protection Against Delayed Cerebral Ischemia in Subarachnoid Hemorrhage in Response to Hypoxic Postconditioning.
Sirtuin 1 Mediates Protection Against Delayed Cerebral Ischemia in Subarachnoid Hemorrhage in Response to Hypoxic Postconditioning.
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DOI：
10.1161/jaha.121.021113
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发表时间：
2021-10-19
影响因子：
5.4
通讯作者：
Zipfel GJ
中科院分区：
文献类型：
--
作者：
Diwan D;Vellimana AK;Aum DJ;Clarke J;Nelson JW;Lawrence M;Han BH;Gidday JM;Zipfel GJ
许多旨在预防迟发性脑缺血(DCI)和改善动脉瘤性蛛网膜下腔出血(SAH)神经预后的治疗方法都失败了，可能是因为只针对已被证明是多因素疾病的一种因素。我们先前证明，在低氧预适应(SAH)之前启动低氧适应可以有效地预防DCI。在这里，我们对这些发现进行了扩展，以确定在SAH(低氧后处理)后的临床相关时间点提供的低氧适应是否提供了类似的强大的DCI保护。在这项研究中，我们发现SAH后3小时开始的低氧后处理(8%O2持续2小时)对脑血管痉挛、微血管血栓和神经功能缺失有很强的保护作用。通过分别使用EX527和全局Sirt1−/−小鼠对sirt1(Sirtuin1)的药理和遗传抑制，我们证明了这种多方面的DCI保护是由sirt1介导的。此外，使用Sirt1-TG小鼠的SIRT1基因过表达，模拟了低氧后处理提供的DCI保护。最后，我们发现SAH后给予白藜芦醇可以减轻脑血管痉挛、微血管血栓和神经功能障碍，并且这种作用依赖于SIRT1。本研究表明，在临床相关时间点启动低氧后处理可提供强大的DCI保护作用，SAH后SIRT1活性的药理增强可模拟这一有益效果。我们的结论是，SAH后给予的条件性治疗对SAH患者有很好的转化性，值得进一步研究。
Many therapies designed to prevent delayed cerebral ischemia (DCI) and improve neurological outcome in aneurysmal subarachnoid hemorrhage (SAH) have failed, likely because of targeting only one element of what has proven to be a multifactorial disease. We previously demonstrated that initiating hypoxic conditioning before SAH (hypoxic preconditioning) provides powerful protection against DCI. Here, we expanded upon these findings to determine whether hypoxic conditioning delivered at clinically relevant time points after SAH (hypoxic postconditioning) provides similarly robust DCI protection. In this study, we found that hypoxic postconditioning (8% O2 for 2 hours) initiated 3 hours after SAH provides strong protection against cerebral vasospasm, microvessel thrombi, and neurological deficits. By pharmacologic and genetic inhibition of SIRT1 (sirtuin 1) using EX527 and global Sirt1 −/− mice, respectively, we demonstrated that this multifaceted DCI protection is SIRT1 mediated. Moreover, genetic overexpression of SIRT1 using Sirt1‐Tg mice, mimicked the DCI protection afforded by hypoxic postconditioning. Finally, we found that post‐SAH administration of resveratrol attenuated cerebral vasospasm, microvessel thrombi, and neurological deficits, and did so in a SIRT1‐dependent fashion. The present study indicates that hypoxic postconditioning provides powerful DCI protection when initiated at clinically relevant time points, and that pharmacologic augmentation of SIRT1 activity after SAH can mimic this beneficial effect. We conclude that conditioning‐based therapies administered after SAH hold translational promise for patients with SAH and warrant further investigation.
影响因子：
6.9
作者：
Keep RF;Wang MM;Xiang J;Hua Y;Xi G
通讯作者：
Xi G