Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, China.
Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
Neurosci Bull. 2019 Apr;35(2):336-346. doi: 10.1007/s12264-018-0313-8. Epub 2018 Dec 5.
We have previously reported that Cystatin C (CysC) is a pivotal mediator in the neuroprotection induced by hyperbaric oxygen (HBO) preconditioning; however, the underlying mechanism and how CysC changes after stroke are not clear. In the present study, we demonstrated that CysC expression was elevated as early as 3 h after reperfusion, and this was further enhanced by HBO preconditioning. Concurrently, LC3-II and Beclin-1, two positive-markers for autophagy induction, exhibited increases similar to CysC, while knockdown of CysC blocked these elevations. As a marker of autophagy inhibition, p62 was downregulated by HBO preconditioning and this was blocked by CysC knockdown. Besides, the beneficial effects of preserving lysosomal membrane integrity and enhancing autolysosome formation induced by HBO preconditioning were abolished in CysC rats. Furthermore, we demonstrated that exogenous CysC reduced the neurological deficits and infarct volume after brain ischemic injury, while 3-methyladenine partially reversed this neuroprotection. In the present study, we showed that CysC is biochemically and morphologically essential for promoting autophagic flux, and highlighted the translational potential of HBO preconditioning and CysC for stroke treatment.
我们之前曾报道过胱抑素 C（CysC）是高压氧（HBO）预处理诱导神经保护的关键介质；然而，其潜在机制以及中风后 CysC 如何变化尚不清楚。在本研究中，我们证实 CysC 的表达在再灌注后 3 小时即可升高，而 HBO 预处理可进一步增强其表达。同时，LC3-II 和 Beclin-1，自噬诱导的两个阳性标志物，其表达也与 CysC 相似增加，而 CysC 的敲低则阻断了这些增加。作为自噬抑制的标志物，p62 被 HBO 预处理下调，而 CysC 的敲低则阻断了这一下调。此外，HBO 预处理诱导的溶酶体膜完整性的保护和自噬溶酶体形成的增强作用在 CysC 大鼠中被消除。此外，我们还证实外源性 CysC 可减少脑缺血损伤后的神经功能缺损和梗死体积，而 3-甲基腺嘌呤可部分逆转这种神经保护作用。在本研究中，我们表明 CysC 在促进自噬流方面具有生化和形态学上的重要性，并强调了 HBO 预处理和 CysC 在中风治疗中的转化潜力。
