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H2S Regulates the Phenotypic Transformation of Astrocytes Following Cerebral Ischemia/Reperfusion via Inhibiting the RhoA/ROCK Pathway

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Abstract

The role of hydrogen sulfide (H2S) on the phenotypic change of astrocytes following cerebral ischemia/reperfusion (I/R) in mice was investigated in present study. We tested the expression of glial fibrillary acidic protein (GFAP), A2 phenotype marker S100a10, and A1 phenotype marker C3 protein and assessed the change of BrdU/GFAP-positive cells, GFAP/C3-positive cells, and GFAP/S100a10-positive cells in mice hippocampal tissues to evaluate the change of astrocyte phenotypes following cerebral I/R. The role of H2S on the phenotypic change of astrocytes following cerebral I/R in mice was investigated by using H2S synthase cystathionine-γ-lyase (CSE) knockout mice (KO). The results revealed that cerebral I/R injury promoted the astrocytes proliferation of both A1 and A2 phenotypes, which were more significant in mice of H2S synthase CSE KO than in mice of wild type (WT). Interestingly, supplement with H2S could inhibit the A1 phenotype proliferation but promote the proliferation of A2 phenotype, suggesting that H2S could regulate the transformation of astrocytes to A2 phenotype following cerebral I/R, which is beneficial for neuronal recovery. Besides, we found that H2S-mediated change of astrocyte phenotype is related to inhibiting the RhoA/ROCK pathway. Furthermore, both H2S and ROCK inhibitor could ameliorate the brain injury of mice at 9 days after cerebral I/R. In conclusion, H2S regulates the phenotypic transformation of astrocytes to A2 phenotype following the cerebral I/R via inhibiting RhoA/ROCK pathway and then exerts the neuroprotective effect against the subacute brain injury.

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Data Availability

The data and materials are available on reasonable request.

Abbreviations

WT:

Wild type

CSE KO:

CSE knockout

CCAs:

Bilateral common carotid arteries

GFAP:

Glial fibrillary acidic protein

ROCK:

Rho kinase

CNS:

Cerebral nervous system

H2S:

Hydrogen sulfide

CO:

Monoxide

NO:

Nitric oxide

CSE:

Cystathionine γ-lyase

CBS:

Cystathionine β-synthase

3-MST:

3-Mercaptopyruvate sulfurtransferase

BrdU:

Bromodeoxyuridine

OFT:

Open-field test

MWM:

Morris water maze

H&E:

Hematoxylin and eosin staining

NSE:

Neuron-specific enolase

LDH:

Lactate dehydrogenase

PAGE:

SDS-polyacrylamide gel electrophoresis

PVDF:

Polyvinylidene difluoride

DAPI:

Anti-4′,6-diamidino-2-phenylindole

MBP:

Myelin basic protein

NeuN:

Neuronal nuclei

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Funding

This study was supported by Natural Science Foundation of Colleges and Universities in Anhui Province (No. 2023AH050672) and Natural Science Foundation of Anhui Province (NO. 2308085MH302).

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Author notes

  1. Yanyu Ding and Fang Fang contributed equally.

Authors and Affiliations

  1. Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China

    Yanyu Ding, Xiaolong Liu, Shuyan Sheng, Xueyan Li, Xiaojiao Yin, Zhiwu Chen & Jiyue Wen

  2. Department of Pharmacy, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China

    Fang Fang

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Contributions

JW and ZC designed the manuscript. YD, XL, and FF carried out experiments and wrote the manuscript. XL and XY performed the behavioral experiments in mice. YD performed the ELISA and analyzed the data. SS, JW, and ZC contributed to funding acquisition, supervision, and editing.

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Correspondence to Zhiwu Chen or Jiyue Wen.

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The animal experiments were approved by the Ethical Committee of Anhui Medical University, and all experimental protocols complied with the regulations set by animal care and use committee in Anhui Medical University, which comply with the protocol outlined in the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication no. 85–23, revised 2011).

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Ding, Y., Fang, F., Liu, X. et al. H2S Regulates the Phenotypic Transformation of Astrocytes Following Cerebral Ischemia/Reperfusion via Inhibiting the RhoA/ROCK Pathway. Mol Neurobiol 61, 3179–3197 (2024). https://doi.org/10.1007/s12035-023-03797-8

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