SIRT6 promotes angiogenesis by enhancing VEGFA secretion via demyristoylation in endothelial cell

Runyang Feng; Shuangshuang Chen; Shichao Duan; Zhenyang Guo; Na Wu; Hangnan Hong; Zheyan Fang; Litao Wang; Yuxin Du; Lin Wu; Xin Zhong; Yiqing Hu; Zhentao Zhang; Mukaddas Abdurahman; Peng Li; Hua Li; Junbo Ge

doi:10.1016/j.yjmcc.2024.12.006

SIRT6 promotes angiogenesis by enhancing VEGFA secretion via demyristoylation in endothelial cell

J Mol Cell Cardiol. 2025 Jan 2:S0022-2828(24)00211-6. doi: 10.1016/j.yjmcc.2024.12.006. Online ahead of print.

Authors

Runyang Feng¹, Shuangshuang Chen², Shichao Duan³, Zhenyang Guo¹, Na Wu¹, Hangnan Hong¹, Zheyan Fang¹, Litao Wang¹, Yuxin Du¹, Lin Wu¹, Xin Zhong¹, Yiqing Hu¹, Zhentao Zhang¹, Mukaddas Abdurahman¹, Peng Li⁴, Hua Li⁵, Junbo Ge⁶

Affiliations

¹ Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai 200032, China.
² Ministry of Education Key Laboratory of Metabolism and Molecular Medicine, Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China.
³ Henan Provincial People's Hospital, Henan Eye Hospital, Henan Eye Institute, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan 450003, China.
⁴ Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai 200032, China. Electronic address: [email protected].
⁵ Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai 200032, China. Electronic address: [email protected].
⁶ Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai 200032, China; State Key Laboratory of Cardiology, Zhongshan Hospital, Fudan University, China; Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, China; Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, China; National Clinical Research Center for Interventional Medicine, Shanghai, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, China. Electronic address: [email protected].

PMID: 39753390
DOI: 10.1016/j.yjmcc.2024.12.006

Abstract

Angiogenesis plays a pivotal role in ischemic cardiovascular disease, accompanied by epigenetic regulation during this process. Sirtuin 6 (SIRT6) has been implicated in the regulation of DNA repair, transcription and aging, with its deacetylase activity fully studied. However, the role of SIRT6 demyristoylase activity remains less clear, with even less attention given to its myristoylated substrates. In this study, we report that endothelial specific SIRT6 knockout attenuated angiogenesis in mice, while SIRT6 was observed to promote migration and tube formation in endothelial cell. Notably, we further determined that SIRT6 affects the intracellular VEGFA and global myristoylation level under hypoxia. Moreover, ALK14 (myristic acids analogue) treatment and SIRT6 knockdown results in a significant decrease in VEGFA secretion under hypoxia, implying the involvement of SIRT6 demyristoylase activity in angiogenesis. Mechanistically, CLICK IT assay verified that VEGFA is a myristoylated substrate of SIRT6. Further, overexpression of SIRT6 mutants (R65A, G60A and H133Y) results in profound differences in VEGFA secretion, indicating that SIRT6 promotes VEGFA secretion through demyristoylation but not deacetylation. Finally, overexpression of SIRT6 rescued the diminishment of endothelial migration, tube formation and sprouting caused by ALK14 treatment. Overall, our study demonstrates that SIRT6 regulates angiogenesis by demyristoylating VEGFA and increasing VEGFA secretion. Therefore, modulation of SIRT6 demyristoylase activity may represent a therapeutic strategy for ischemic cardiovascular disease.

Keywords: Angiogenesis; Defatty-acylation; Myristoylation; SIRT6; VEGFA.