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Hydrogen sulphide reduces hyperhomocysteinaemia-induced endothelial ER stress by sulfhydrating protein disulphide isomerase to attenuate atherosclerosis |
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| Authors: | Shan Jiang Wenjing Xu Zhenzhen Chen Changting Cui Xiaofang Fan Jun Cai Yongsheng Gong Bin Geng |
| Affiliation: | 1. Institute of Hypoxia Medicine, Wenzhou Medical University, Zhejiang, China Contribution: Conceptualization (equal), Data curation (equal), Formal analysis (equal), Investigation (equal), Methodology (equal), Writing - original draft (equal);2. Department of Pathology, Xi'an Medical University, Shanxi, China Contribution: Data curation (equal), Formal analysis (equal), Investigation (equal), Writing - original draft (equal);3. State Key Laboratory of Cardiovascular Disease, Hypertension Center, National Center for Cardiovascular Diseases, Fuwai Hospital of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Contribution: Funding acquisition (equal), Methodology (equal), Validation (equal);4. State Key Laboratory of Cardiovascular Disease, Hypertension Center, National Center for Cardiovascular Diseases, Fuwai Hospital of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Contribution: Data curation (equal), Formal analysis (equal), Methodology (equal), Validation (equal);5. Institute of Hypoxia Medicine, Wenzhou Medical University, Zhejiang, China Contribution: Methodology (equal), Resources (equal), Supervision (equal);6. State Key Laboratory of Cardiovascular Disease, Hypertension Center, National Center for Cardiovascular Diseases, Fuwai Hospital of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Contribution: Funding acquisition (equal), Investigation (equal), Resources (equal), Supervision (equal);7. Institute of Hypoxia Medicine, Wenzhou Medical University, Zhejiang, China |
| Abstract: | Hyperhomocysteinaemia (HHcy)-impaired endothelial dysfunction including endoplasmic reticulum (ER) stress plays a crucial role in atherogenesis. Hydrogen sulphide (H2S), a metabolic production of Hcy and gasotransmitter, exhibits preventing cardiovascular damages induced by HHcy by reducing ER stress, but the underlying mechanism is unclear. Here, we made an atherosclerosis with HHcy mice model by ApoE knockout mice and feeding Pagien diet and drinking L-methionine water. H2S donors NaHS and GYY4137 treatment lowered plaque area and ER stress in this model. Protein disulphide isomerase (PDI), a modulation protein folding key enzyme, was up-regulated in plaque and reduced by H2S treatment. In cultured human aortic endothelial cells, Hcy dose and time dependently elevated PDI expression, but inhibited its activity, and which were rescued by H2S. H2S and its endogenous generation key enzyme-cystathionine γ lyase induced a new post-translational modification-sulfhydration of PDI. Sulfhydrated PDI enhanced its activity, and two cysteine-terminal CXXC domain of PDI was identified by site mutation. HHcy lowered PDI sulfhydration association ER stress, and H2S rescued it but this effect was blocked by cysteine site mutation. Conclusively, we demonstrated that H2S sulfhydrated PDI and enhanced its activity, reducing HHcy-induced endothelial ER stress to attenuate atherosclerosis development. |
| Keywords: | atherosclerosis endoplasmic reticulum stress homocysteine hydrogen sulphide protein disulphide isomerase sulfhydration |