SIRT6 Lysine-Demyristoylates ATF2 to Ameliorate Vascular Injury via PRKCD/VE-Cadherin Pathway Regulating Vascular Endothelial Barrier

Runyang Feng¹, Zheyan Fang¹, Shuang Zhao², You-En Zhang³, Na Wu⁴, Zhenyang Guo¹, Xin Zhong¹, Bixuan Jiang^{5

6}, Hongfei Xu⁷, Hangnan Hong¹, Zhentao Zhang¹, Mukaddas Abdurahman¹, Xueting Yu¹, Jilong Geng¹, Xiansu Nie¹, Supuya Abuduwahapi¹, Dong Huang¹, Gang Zhao¹, Wenbin Zhang⁸, Hao Lu¹, Li Shen¹, Xin Zhao¹, Zhaoyang Chen⁹, Junjie Guo¹⁰, Hongchao Zheng⁴, Yue He¹¹, Sanwu Wu³, Jiayin Peng¹², Jiawen Song¹², Xiao Wang^{13

14}, Haomin Li¹⁵, Yuli Huang¹⁶, Shengying Qin⁵, Haojie Lu¹⁷, Xiangdong Wang¹⁸, Jianguo Zhao^{14

19

20}, Lei Huang²¹, Yun Zhao^{12

22

23}, Peng Li¹, Junbo Ge^{1

24

25

26

27

28

29}, Hua Li¹

Affiliations

¹ Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases, Fudan University, Shanghai, 200032, China.
² Department of Medical Examination, Shanghai Xuhui District Central Hospital, Shanghai, 200031, China.
³ Department of Cardiology, Arteriosclerosis Cardiovascular Disease Clinical Medical Research Center of Hubei Province, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, China.
⁴ Department of Cardiology, Shanghai Xuhui District Central Hospital, Shanghai, 200031, China.
⁵ Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 200030, China.
⁶ School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China.
⁷ Department of Forensic Medicine, Soochow University, Suzhou, 215000, China.
⁸ Department of Cardiology, Sir Run Run Shaw Hospital, affiliated with Zhejiang University School of Medicine, Hangzhou, 310020, China.
⁹ Department of Cardiology, Heart Center of Fujian Province, Fujian Medical University Union Hospital, Fuzhou, 350001, China.
¹⁰ Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China.
¹¹ Department of Cardiology, Shanghai Eighth People's Hospital, Shanghai, 200235, China.
¹² State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China.
¹³ State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193, China.
¹⁴ State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
¹⁵ Clinical Data Center, the Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, 310052, China.
¹⁶ Department of Cardiology, Shunde Hospital, Southern Medical University, Guangdong, 528399, China.
¹⁷ Department of Chemistry and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
¹⁸ Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
¹⁹ Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 100049, China.
²⁰ Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
²¹ Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
²² School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai, 201210, China.
²³ Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
²⁴ National Basic Science Center for Complex System of Panvascular Intervention, Shanghai, 200032, China.
²⁵ National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China.
²⁶ Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
²⁷ Shanghai Clinical Research Center for Interventional Medicine, Shanghai, 200032, China.
²⁸ Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, 200032, China.
²⁹ Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, 200032, China.

PMID: 40810740
DOI: 10.1002/advs.202504948

SIRT6 Lysine-Demyristoylates ATF2 to Ameliorate Vascular Injury via PRKCD/VE-Cadherin Pathway Regulating Vascular Endothelial Barrier

Runyang Feng et al. Adv Sci (Weinh). 2025.

. 2025 Aug 14:e04948.

doi: 10.1002/advs.202504948. Online ahead of print.

Authors

Affiliations

¹ Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases, Fudan University, Shanghai, 200032, China.
² Department of Medical Examination, Shanghai Xuhui District Central Hospital, Shanghai, 200031, China.
³ Department of Cardiology, Arteriosclerosis Cardiovascular Disease Clinical Medical Research Center of Hubei Province, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, China.
⁴ Department of Cardiology, Shanghai Xuhui District Central Hospital, Shanghai, 200031, China.
⁵ Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 200030, China.
⁶ School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China.
⁷ Department of Forensic Medicine, Soochow University, Suzhou, 215000, China.
⁸ Department of Cardiology, Sir Run Run Shaw Hospital, affiliated with Zhejiang University School of Medicine, Hangzhou, 310020, China.
⁹ Department of Cardiology, Heart Center of Fujian Province, Fujian Medical University Union Hospital, Fuzhou, 350001, China.
¹⁰ Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China.
¹¹ Department of Cardiology, Shanghai Eighth People's Hospital, Shanghai, 200235, China.
¹² State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China.
¹³ State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, 100193, China.
¹⁴ State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
¹⁵ Clinical Data Center, the Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, 310052, China.
¹⁶ Department of Cardiology, Shunde Hospital, Southern Medical University, Guangdong, 528399, China.
¹⁷ Department of Chemistry and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
¹⁸ Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
¹⁹ Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 100049, China.
²⁰ Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
²¹ Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
²² School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai, 201210, China.
²³ Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
²⁴ National Basic Science Center for Complex System of Panvascular Intervention, Shanghai, 200032, China.
²⁵ National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China.
²⁶ Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
²⁷ Shanghai Clinical Research Center for Interventional Medicine, Shanghai, 200032, China.
²⁸ Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, 200032, China.
²⁹ Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, 200032, China.

PMID: 40810740
DOI: 10.1002/advs.202504948

Abstract

Cardiovascular diseases (CVDs) progression is significantly modulated by epigenetic mechanisms, particularly through Sirtuin 6 (SIRT6), a key NAD⁺-dependent deacetylase in the sirtuin family. Though essential for cardiovascular homeostasis, the effects of SIRT6-mediated lysine myristoylation on CVDs progression remain largely unexplored due to detection limitations. This study developes an innovative lysine-myristoylated peptide enrichment technique, identifying mutant SIRT6 (H133Y) with high myristoyl affinity but deficient demyristoylase activity. This advancement enables identification of 15 previously unrecognized human lysine-myristoylated proteins. Further study demonstrates that SIRT6 demyristoylates activating transcription factor 2 (ATF2) at K296 and regulates its nucleoplasmic translocation. Through 4D label-free mass spectrometry and molecular approaches, it is revealed that decreased nuclear localization of ATF2 results in reduced Protein kinase C delta type (PRKCD) expression, establishing a SIRT6/Myr-ATF2/PRKCD/VE-Cadherin pathway that enhances endothelial barrier integrity under high myristate conditions. These findings are validated in vitro (gene overexpression/knockdown cells) and in vivo (SIRT6 knockout/double-transgenic mice). The study provides both a novel method for identifying lysine-myristoylated proteins and critical insights into SIRT6 demyristoylation biology. Modulating the SIRT6 pathway might yield therapies to strengthen endothelial integrity and mitigate vascular dysfunction in CVDs, offering promising clinical translation avenues.

Keywords: ATF2; SIRT6; endothelial barrier function; epigenetic regulation; myristoylation; nucleoplasmic translocation.

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References

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82170334 82470337/National Natural Science Foundation of China

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SIRT6 Lysine-Demyristoylates ATF2 to Ameliorate Vascular Injury via PRKCD/VE-Cadherin Pathway Regulating Vascular Endothelial Barrier

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SIRT6 Lysine-Demyristoylates ATF2 to Ameliorate Vascular Injury via PRKCD/VE-Cadherin Pathway Regulating Vascular Endothelial Barrier

Authors

Affiliations

Abstract

References

Grants and funding

LinkOut - more resources

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