Translocation of SIRT6 promotes glycolysis reprogramming to exacerbate diabetic angiopathy
Kemiao Pang,
Jiayi Huang,
Shiwu Zhang,
Yinghui Guan,
Ning Zou,
Jiaxin Kang,
Haining Du,
Dechao Zhao,
Denis V. Abramochkin,
Heyu Chen,
Nan Zhang,
Yunyan Gu,
Ning Liu,
Yining Niu,
Ziqi Xiong,
Xueya Zhang,
Fanghao Lu,
Huitao Fan,
Jinwei Tian,
Bo Yu,
Shuijie Li,
Weihua Zhang
Affiliations
Kemiao Pang
Department of Cardiology, Department of Pathophysiology, Key Laboratory of Myocardial Ischemia, Ministry of Education, Second Affiliated Hospital of Harbin Medical University, China
Jiayi Huang
Department of Cardiology, Department of Pathophysiology, Key Laboratory of Myocardial Ischemia, Ministry of Education, Second Affiliated Hospital of Harbin Medical University, China
Shiwu Zhang
Department of Cardiology, Department of Pathophysiology, Key Laboratory of Myocardial Ischemia, Ministry of Education, Second Affiliated Hospital of Harbin Medical University, China
Yinghui Guan
Department of Vascular Surgery, First Affiliated Hospital of Harbin Medical University, China
Ning Zou
Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, China
Jiaxin Kang
Department of Cardiology, Department of Pathophysiology, Key Laboratory of Myocardial Ischemia, Ministry of Education, Second Affiliated Hospital of Harbin Medical University, China
Haining Du
Department of Cardiology, Department of Pathophysiology, Key Laboratory of Myocardial Ischemia, Ministry of Education, Second Affiliated Hospital of Harbin Medical University, China
Dechao Zhao
Department of Cardiology, First Affiliated Hospital of Harbin Medical University, China
Denis V. Abramochkin
Department of Human and Animal Physiology, Biological Faculty, Lomonosov Moscow State University, Russia
Heyu Chen
Department of Cardiology, Department of Pathophysiology, Key Laboratory of Myocardial Ischemia, Ministry of Education, Second Affiliated Hospital of Harbin Medical University, China
Nan Zhang
College of Bioinformatics Science and Technology, Harbin Medical University, China
Yunyan Gu
College of Bioinformatics Science and Technology, Harbin Medical University, China
Ning Liu
Department of Cardiology, Department of Pathophysiology, Key Laboratory of Myocardial Ischemia, Ministry of Education, Second Affiliated Hospital of Harbin Medical University, China
Yining Niu
Department of Cardiology, Department of Pathophysiology, Key Laboratory of Myocardial Ischemia, Ministry of Education, Second Affiliated Hospital of Harbin Medical University, China
Ziqi Xiong
Department of Cardiology, Department of Pathophysiology, Key Laboratory of Myocardial Ischemia, Ministry of Education, Second Affiliated Hospital of Harbin Medical University, China
Xueya Zhang
Department of Cardiology, Department of Pathophysiology, Key Laboratory of Myocardial Ischemia, Ministry of Education, Second Affiliated Hospital of Harbin Medical University, China
Fanghao Lu
Department of Cardiology, Department of Pathophysiology, Key Laboratory of Myocardial Ischemia, Ministry of Education, Second Affiliated Hospital of Harbin Medical University, China
Huitao Fan
NHC Key Laboratory of Cell Transplantation, The First Affiliated Hospital of Harbin Medical University, China; Department of Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, China; Department of Hematology, The First Affiliated Hospital of Harbin Medical University, China; Corresponding author. Department of Hematology, The First Affiliated Hospital of Harbin Medical University, China.
Jinwei Tian
Department of Cardiology, Department of Pathophysiology, Key Laboratory of Myocardial Ischemia, Ministry of Education, Second Affiliated Hospital of Harbin Medical University, China; Heilongjiang Provincial Key Laboratory of Panvascular Disease, China; Corresponding author. Department of Cardiology, Department of Pathophysiology, Key Laboratory of Myocardial Ischemia, Ministry of Education, Second Affiliated Hospital of Harbin Medical University, China.
Bo Yu
Department of Cardiology, Department of Pathophysiology, Key Laboratory of Myocardial Ischemia, Ministry of Education, Second Affiliated Hospital of Harbin Medical University, China; State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), China; Corresponding authors. State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), China.
Shuijie Li
State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), China; Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, China; Heilongjiang Province Key Laboratory of Research on Molecular Targeted Antitumor Drugs, China; Corresponding authors. State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), China.
Weihua Zhang
Department of Cardiology, Department of Pathophysiology, Key Laboratory of Myocardial Ischemia, Ministry of Education, Second Affiliated Hospital of Harbin Medical University, China; Heilongjiang Provincial Key Laboratory of Panvascular Disease, China; Corresponding authors. Department of Cardiology, Department of Pathophysiology, Key Laboratory of Myocardial Ischemia, Ministry of Education, Second Affiliated Hospital of Harbin Medical University, China.
Diabetic angiopathy, a major complication of type 2 diabetes mellitus (T2DM), is driven by vascular dysfunction, metabolic reprogramming, and oxidative stress. NAD+-dependent deacetylase SIRT6, located in the nucleus, is recognized for its role in modulating cardiovascular and metabolic homeostasis through histone deacetylation. However, the functions and mechanisms of accumulation of cytoplasmic SIRT6 in T2DM remain to be elucidated. Herein, a previously unrecognized cytoplasmic role for SIRT6 is identified in promoting pathological glycolysis during diabetic vascular remodeling. Vascular smooth muscle cell (VSMC) proliferation is observed, which is correlated with protein deacetylation, especially SIRT6, which translocated to the cytoplasm mediated by Importin 13 (IPO13). Furthermore, the accumulation of cytoplasmic SIRT6 facilitates its interaction with enolase 3 (ENO3), a newly discovered downstream target. This interaction promotes ENO3 deacetylation, enhances downstream phosphoenolpyruvic acid (PEP) levels, and thereby drives glycolysis reprogramming, ultimately leading to the pathological changes associated with diabetic angiopathy. Notably, exogenous hydrogen sulfide (H2S) restores S-sulfhydration of SIRT6 at cysteine 141, counteracting the SIRT6-ENO3 interaction, suppressing glycolysis, and mitigating VSMC hyperproliferation. This study provides novel insights into the SIRT6-ENO3 pathway through regulating vascular glycolysis reprogramming, highlighting the therapeutic potential of targeting SIRT6 in the management of diabetic angiopathy.
