Volume 35, Issue. 2, April, 2019


Neuroprotective Autophagic Flux Induced by Hyperbaric Oxygen Preconditioning is Mediated by Cystatin C

Zongping Fang1 • Yun Feng2 • Yuheng Li1 • Jiao Deng1 • Huang Nie1 • Qianzhi Yang1 • Shiquan Wang1 • Hailong Dong1,* • Lize Xiong1,*

1Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, The Fourth Military Medical University, Xi’an 710032, China
2Department of Gastroenterology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China

Abstract

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.

Keywords

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