journal article·2025-11Open access

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

Runyang Feng, Zheyan Fang, Shuang Zhao, You‐en Zhang, Na Wu, Zhenyang Guo, Xin Zhong, Bixuan Jiang, Hongfei Xu, Hangnan Hong, Zhentao Zhang, Mukaddas Abdurahman, Xueting Yu, Jilong Geng, Xiansu Nie, Supuya Abuduwahapi, Dong Huang, Gang Zhao, Wenbin Zhang, Hao Lu, Li Shen, Xin Zhao, Zhaoyang Chen, Junjie Guo, Hongchao Zheng, Yue He, Sanwu Wu, Jiayin Peng, Jiawen Song, Xiao Wang, Haomin Li, Yuli Huang, Shengying Qin, Haojie Lu, Xiangdong Wang, Jianguo Zhao, Lei Huang, Yun Zhao, Peng Li, Junbo Ge, Hua Li

Advanced Science· Volume 12· Issue 41

Abstract

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.
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Research context

OpenAlex topics: Neurological Disorders and Treatments

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Cardiology Zhongshan Hospital Shanghai Institute of Cardiovascular Diseases Fudan University Shanghai 200032 China

Department of Medical Examination Shanghai Xuhui District Central Hospital Shanghai 200031 China

Department of Cardiology Arteriosclerosis Cardiovascular Disease Clinical Medical Research Center of Hubei Province Renmin Hospital Hubei University of Medicine Shiyan Hubei 442000 China

Department of Cardiology Shanghai Xuhui District Central Hospital Shanghai 200031 China

Bio‐X Institutes Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education) Shanghai Jiao Tong University Shanghai 200030 China

School of Life Sciences and Biotechnology Shanghai Jiao Tong University Shanghai 200240 China

Department of Forensic Medicine Soochow University Suzhou 215000 China

Department of Cardiology Sir Run Run Shaw Hospital affiliated with Zhejiang University School of Medicine Hangzhou 310020 China

Department of Cardiology Heart Center of Fujian Province Fujian Medical University Union Hospital Fuzhou 350001 China

Department of Cardiology The Affiliated Hospital of Qingdao University Qingdao 266003 China

Department of Cardiology Shanghai Eighth People's Hospital Shanghai 200235 China

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

State Key Laboratory of Animal Nutrition Institute of Animal Science Chinese Academy of Agricultural Sciences Beijing 100193 China

State Key Laboratory of Stem Cell and Reproductive Biology Institute of Zoology Chinese Academy of Sciences Beijing 100101 China

Clinical Data Center the Children's Hospital, Zhejiang University School of Medicine National Clinical Research Center for Child Health Hangzhou Zhejiang 310052 China

Department of Cardiology Shunde Hospital Southern Medical University Guangdong 528399 China

Department of Chemistry and Institutes of Biomedical Sciences Fudan University Shanghai 200032 China

Department of Pulmonary and Critical Care Medicine Zhongshan Hospital Shanghai Medical College Fudan University Shanghai 200032 China

Savaid Medical School University of Chinese Academy of Sciences Beijing 100049 China

Beijing Institute for Stem Cell and Regenerative Medicine Beijing 100101 China

Department of Molecular Cell and Cancer Biology University of Massachusetts Chan Medical School Worcester MA 01605 USA

School of Life Science and Technology ShanghaiTech University 100 Haike Road Shanghai 201210 China

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

National Basic Science Center for Complex System of Panvascular Intervention Shanghai 200032 China

National Clinical Research Center for Interventional Medicine Shanghai 200032 China

Funding

National Natural Science Foundation of China

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