Hydrogen sulfide ameliorates subarachnoid hemorrhage-induced neuronal apoptosis via the ROS-MST1 pathway.

Ligen Shi,Yucong Peng,Jianmin Zhang,Jun Yu,Yan Wang,Jianwei Lei,Hangzhe Xu,Jingwei Zheng

doi:10.18632/oncotarget.20569

Ligen Shi, Yucong Peng + Show 6 more

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https://doi.org/10.18632/oncotarget.20569

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Abstract

BackgroundHydrogen sulfide (H2S) has shown a neuroprotective role in several cerebrovascular diseases. This study aimed to explore the underlying mechanisms of H2S in early brain injury after subarachnoid hemorrhage (SAH).MethodsOne hundred seventy-seven male Sprague-Dawley rats were employed in this study. Sodium hydrosulfide (NaHS), a donor of H2S, was injected intraperitoneally at 60 min after SAH was induced by endovascular perforation. Western blot analysis determined the expression of several proteins of interest, and an immunofluorescence assay was used to examine neuronal apoptosis.ResultsExogenous NaHS markedly improved neurological scores, attenuated brain edema, and ameliorated neuronal apoptosis at 24 h after SAH induction. The underlying mechanisms of H2S in ameliorating neuronal apoptosis might be executed through inhibition of the activity of mammalian sterile 20-like kinase 1 (MST1) protein. Western blot analysis demonstrated that exogenous NaHS decreased cleaved MST1 (cl-MST1) while increasing full-length MST1 expression. This anti-apoptotic effect of H2S could be reversed by chelerythrine, which could activate MST1 via caspase-dependent cleavage.ConclusionsExogenous NaHS, as a donor of H2S, could ameliorate early brain injury after SAH by inhibiting neuronal apoptosis by reducing the activity of the MST1 protein.

Highlights

Aneurysmal subarachnoid hemorrhage (SAH) is a common and severe subtype of hemorrhagic stroke with a high mortality [1]
mammalian sterile 20-like kinase 1 (MST1) protein was mainly expressed in the cytoplasm of neuronal cells
The results showed that MST1 was primarily expressed in the cytoplasm of neuronal cells

Summary

Introduction

Aneurysmal subarachnoid hemorrhage (SAH) is a common and severe subtype of hemorrhagic stroke with a high mortality [1]. Among multiple complex mechanisms of EBI after SAH, apoptosis is regarded as one of the most crucial factors that may be associated with delayed neurological deterioration and poor longterm outcomes [3]. Previous studies have indicated that oxidative stress activates MST1 and simultaneously cleaves MST1 to produce a 36 kDa N-terminal constitutively active fragment (cl-MST1) [9]. This cl-MST1 has a 10-fold higher activity than the full-length Mst kinase [9]. Agents that can inhibit the ROS-MST1-induced cell apoptosis pathway may be an alternative anti-apoptotic agent for EBI after SAH. This study aimed to explore the underlying mechanisms of H2S in early brain injury after subarachnoid hemorrhage (SAH)

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