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Published Online: 10 April 2013

Hydrogen Sulfide Protects Against Cellular Senescence via S-Sulfhydration of Keap1 and Activation of Nrf2

Publication: Antioxidants & Redox Signaling
Volume 18, Issue Number 15

Abstract

Aims: H2S, a third member of gasotransmitter family along with nitric oxide and carbon monoxide, exerts a wide range of cellular and molecular actions in our body. Cystathionine gamma-lyase (CSE) is a major H2S-generating enzyme in our body. Aging at the cellular level, known as cellular senescence, can result from increases in oxidative stress. The aim of this study was to investigate how H2S attenuates oxidative stress and delays cellular senescence. Results: Here we showed that mouse embryonic fibroblasts isolated from CSE knockout mice (CSE KO-MEFs) display increased oxidative stress and accelerated cellular senescence in comparison with MEFs from wild-type mice (WT-MEFs). The protein expression of p53 and p21 was significantly increased in KO-MEFs, and knockdown of p53 or p21 reversed CSE deficiency-induced senescence. Incubation of the cells with NaHS (a H2S donor) significantly increased the glutathione (GSH) level and rescued KO-MEFs from senescence. Nrf2 is a master regulator of the antioxidant response, and Keap1 acts as a negative regulator of Nrf2. NaHS S-sulfhydrated Keap1 at cysteine-151, induced Nrf2 dissociation from Keap1, enhanced Nrf2 nuclear translocation, and stimulated mRNA expression of Nrf2-targeted downstream genes, such as glutamate–cysteine ligase and GSH reductase. Innovation: These results provide a mechanistic insight into how H2S signaling mediates cellular senescence induced by oxidative stress. Conclusion: H2S protects against cellular aging via S-sulfhydration of Keap1 and Nrf2 activation in association with oxidative stress. Antioxid. Redox Signal. 18, 1906–1919.

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cover image Antioxidants & Redox Signaling
Antioxidants & Redox Signaling
Volume 18Issue Number 15May 20, 2013
Pages: 1906 - 1919
PubMed: 23176571

History

Published in print: May 20, 2013
Published online: 10 April 2013
Published ahead of print: 7 February 2013
Published ahead of production: 23 November 2012
Accepted: 21 November 2012
Revision received: 8 November 2012
Received: 12 April 2012

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Guangdong Yang
Cardiovascular and Metabolic Research Unit, Lakehead University, Ontario, Canada.
The School of Kinesiology, Lakehead University, Ontario, Canada.
Kexin Zhao
Cardiovascular and Metabolic Research Unit, Lakehead University, Ontario, Canada.
The School of Kinesiology, Lakehead University, Ontario, Canada.
Youngjun Ju
Cardiovascular and Metabolic Research Unit, Lakehead University, Ontario, Canada.
The School of Kinesiology, Lakehead University, Ontario, Canada.
Sarathi Mani
Cardiovascular and Metabolic Research Unit, Lakehead University, Ontario, Canada.
Department of Biology, Lakehead University, Ontario, Canada.
Qiuhui Cao
Cardiovascular and Metabolic Research Unit, Lakehead University, Ontario, Canada.
Department of Health Sciences, Lakehead University, Ontario, Canada.
Stephanie Puukila
Department of Biology, Lakehead University, Ontario, Canada.
Neelam Khaper
Northern Ontario School of Medicine, Lakehead University, Ontario, Canada.
Lingyun Wu
Cardiovascular and Metabolic Research Unit, Lakehead University, Ontario, Canada.
Department of Health Sciences, Lakehead University, Ontario, Canada.
Rui Wang
Cardiovascular and Metabolic Research Unit, Lakehead University, Ontario, Canada.
Department of Biology, Lakehead University, Ontario, Canada.

Notes

Address correspondence to:Dr. Guangdong YangThe School of KinesiologyLakehead University955 Oliver RoadThunder Bay, Ontario P7B 5E1Canada
E-mail: [email protected]
Dr. Rui WangOffice of Vice PresidentResearch, Economic Development, and InnovationLakehead University955 Oliver RoadThunder Bay, Ontario P7B 5E1Canada
E-mail: [email protected]

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