Hydrogen Sulfide Inhibits High Glucose-Induced Neuronal Senescence by Improving Autophagic Flux via Up-regulation of SIRT1

Lei Wu; Ying Chen; Chun-Yan Wang; Yi-Yun Tang; Hong-Lin Huang; Xuan Kang; Xiang Li; Yu-Rong Xie; Xiao-Qing Tang

doi:10.3389/fnmol.2019.00194

Hydrogen Sulfide Inhibits High Glucose-Induced Neuronal Senescence by Improving Autophagic Flux via Up-regulation of SIRT1

Front Mol Neurosci. 2019 Aug 20:12:194. doi: 10.3389/fnmol.2019.00194. eCollection 2019.

Authors

Lei Wu^{1

2}, Ying Chen^{1

2

3}, Chun-Yan Wang², Yi-Yun Tang¹, Hong-Lin Huang², Xuan Kang⁴, Xiang Li⁴, Yu-Rong Xie⁵, Xiao-Qing Tang^{1

2

4}

Affiliations

¹ Institute of Neuroscience, Hengyang Medical College, University of South China, Hengyang, China.
² Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy and Pharmacology, University of South China, Hengyang, China.
³ Department of Pharmacology, The Central Hospital of Hengyang, Hengyang, China.
⁴ Institute of Neurology, the First Affiliated Hospital, University of South China, Hengyang, China.
⁵ College of Chemistry and Chemical Engineering, University of South China, Hengyang, China.

Abstract

Hyperglycemia, a key characteristic and risk factor for diabetes mellitus (DM), causes neuronal senescence. Hydrogen sulfide (H₂S) is a novel neuroprotectant. The present work was to investigate the potential effect of H₂S on hyperglycemia-induced neuronal senescence and the underlying mechanisms. We found that NaHS, a donor of H₂S, inhibited high glucose (HG)-induced cellular senescence in HT22 cells (an immortalized mouse hippocampal cell line), as evidenced by a decrease in the number of senescence associated-β-galactosidase (SA-β-gal) positive cells, increase in the growth of cells, and down-regulations of senescence mark proteins, p16^INK4a and p21^CIP1. NaHS improved the autophagic flux, which is judged by a decrease in the amount of intracellular autophagosome as well as up-regulations of LC3II/I and P62 in HG-exposed HT22 cells. Furthermore, blocked autophagic flux by chloroquine (CQ) significantly abolished NaHS-exerted improvement in the autophagic flux and suppression in the cellular senescence of GH-exposed HT22 cells, which indicated that H₂S antagonizes HG-induced neuronal senescence by promoting autophagic flux. We also found that NaHS up-regulated the expression of silent mating type information regulation 2 homolog 1 (SIRT1), an important anti-aging protein, in HG-exposed HT22 cells. Furthermore, inhibition of SIRT1 by sirtinol reversed the protection of H₂S against HG-induced autophagic flux blockade and cellular senescence in HT22 cells. These data indicated that H₂S protects HT22 cells against HG-induced neuronal senescence by improving autophagic flux via up-regulation of SIRT1, suggesting H₂S as a potential treatment strategy for hyperglycemia-induced neuronal senescence and neurotoxicity.

Keywords: SIRT1; autophagic flux; high glucose; hydrogen sulfide; neuronal senescence.