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Published Online: 30 November 2018

Sulfhydrated Sirtuin-1 Increasing Its Deacetylation Activity Is an Essential Epigenetics Mechanism of Anti-Atherogenesis by Hydrogen Sulfide

Publication: Antioxidants & Redox Signaling
Volume 30, Issue Number 2

Abstract

Aims: Hydrogen sulfide (H2S) has a protective role in the pathogenesis of atherosclerosis by multiple pathways. Sirtuin-1 (SIRT1) is a histone deacetylase, as an essential mediated longevity gene, and has an anti-atherogenic effect by regulating the acetylation of some functional proteins. Whether SIRT1 is involved in protecting H2S in atherosclerosis and its mechanism remains unclear.
Results: In ApoE-knockout atherosclerosis mice, treatment with an H2S donor (NaHS or GYY4137) reduced atherosclerotic plaque area, macrophage infiltration, aortic inflammation, and plasma lipid level. H2S treatment increased aorta and liver SIRT1 mRNA expression. Overexpression or slicing cystathionine gamma lyase (CSE) also changed intracellular SIRT1 expression. CSE/H2S treatment increased SIRT1 deacetylation in endothelium and hepatocytes and macrophages, then induced deacetylation of its target proteins (P53, P65, and sterol response element binding protein), thereby reducing endothelial and macrophage inflammation and inhibiting macrophage cholesterol uptake and cholesterol de novo synthesis of liver. Also, CSE/H2S induced SIRT1 sulfhydration at its two zinc finger domains, increased its zinc ion binding activity to stabilize the alpha-helix structure, lowered its ubiquitination, and reduced its degradation.
Innovation: H2S is a novel SIRT1 activator by direct sulfhydration. Because SIRT1 has a role in longevity, H2S may be a protector for aging-related diseases.
Conclusion: Endogenous CSE/H2S directly sulfhydrated SIRT1, enhanced SIRT1 binding to zinc ion, then promoted its deacetylation activity, and increased SIRT1 stability, thus reducing atherosclerotic plaque formation.

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Information & Authors

Information

Published In

cover image Antioxidants & Redox Signaling
Antioxidants & Redox Signaling
Volume 30Issue Number 2January 10, 2019
Pages: 184 - 197
PubMed: 29343087

History

Published in print: January 10, 2019
Published online: 30 November 2018
Published ahead of print: 26 February 2018
Published ahead of production: 17 January 2018
Accepted: 17 January 2018
Revision received: 14 January 2018
Received: 1 June 2017

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Congkuo Du*
MOE Key Lab of Cardiovascular Sciences, Department of Physiology and Pathophysiology, Department of Biomedical Informatics, Center for Noncoding RNA Medicine, School of Basic Medical Science, Peking University Health Science Center. Beijing, People's Republic of China.
Xianjuan Lin*
MOE Key Lab of Cardiovascular Sciences, Department of Physiology and Pathophysiology, Department of Biomedical Informatics, Center for Noncoding RNA Medicine, School of Basic Medical Science, Peking University Health Science Center. Beijing, People's Republic of China.
Wenjing Xu*
MOE Key Lab of Cardiovascular Sciences, Department of Physiology and Pathophysiology, Department of Biomedical Informatics, Center for Noncoding RNA Medicine, School of Basic Medical Science, Peking University Health Science Center. Beijing, People's Republic of China.
Fengjiao Zheng
MOE Key Lab of Cardiovascular Sciences, Department of Physiology and Pathophysiology, Department of Biomedical Informatics, Center for Noncoding RNA Medicine, School of Basic Medical Science, Peking University Health Science Center. Beijing, People's Republic of China.
Junyan Cai
MOE Key Lab of Cardiovascular Sciences, Department of Physiology and Pathophysiology, Department of Biomedical Informatics, Center for Noncoding RNA Medicine, School of Basic Medical Science, Peking University Health Science Center. Beijing, People's Republic of China.
Jichun Yang
MOE Key Lab of Cardiovascular Sciences, Department of Physiology and Pathophysiology, Department of Biomedical Informatics, Center for Noncoding RNA Medicine, School of Basic Medical Science, Peking University Health Science Center. Beijing, People's Republic of China.
Qinghua Cui
MOE Key Lab of Cardiovascular Sciences, Department of Physiology and Pathophysiology, Department of Biomedical Informatics, Center for Noncoding RNA Medicine, School of Basic Medical Science, Peking University Health Science Center. Beijing, People's Republic of China.
Chaoshu Tang
MOE Key Lab of Cardiovascular Sciences, Department of Physiology and Pathophysiology, Department of Biomedical Informatics, Center for Noncoding RNA Medicine, School of Basic Medical Science, Peking University Health Science Center. Beijing, People's Republic of China.
Jun Cai
State Key Laboratory of Cardiovascular Disease, Hypertension Center, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.
Guoheng Xu
MOE Key Lab of Cardiovascular Sciences, Department of Physiology and Pathophysiology, Department of Biomedical Informatics, Center for Noncoding RNA Medicine, School of Basic Medical Science, Peking University Health Science Center. Beijing, People's Republic of China.
MOE Key Lab of Cardiovascular Sciences, Department of Physiology and Pathophysiology, Department of Biomedical Informatics, Center for Noncoding RNA Medicine, School of Basic Medical Science, Peking University Health Science Center. Beijing, People's Republic of China.
State Key Laboratory of Cardiovascular Disease, Hypertension Center, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.

Notes

*
These authors contributed equally to this work.
Address correspondence to: Dr. Bin Geng, State Key Laboratory of Cardiovascular Disease, Hypertension Center, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, People's Republic of China [email protected]

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