α-Ketoglutarate promotes cardiomyocyte proliferation and heart regeneration after myocardial infarction

Yu Shi, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P. R. China.
Miao Tian, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P. R. China.
Xiaofang Zhao, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P. R. China.
Luxun Tang, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P. R. China.
Feng Wang, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P. R. China.
Hao Wu, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P. R. China.
Qiao Liao, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P. R. China.
Hongmei Ren, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P. R. China.
Wenbin Fu, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P. R. China.
Shuo Zheng, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P. R. China.
Pedro A. Jose, Division of Renal Diseases and Hypertension, Department of Medicine and Pharmacology-Physiology, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Liangpeng Li, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P. R. China.
Chunyu Zeng, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P. R. China. chunyuzeng01@163.com.

Document Type

Journal Article

Publication Date

9-1-2024

Journal

Nature cardiovascular research

Volume

3

Issue

9

DOI

10.1038/s44161-024-00531-y

Abstract

The neonatal mammalian heart can regenerate following injury through cardiomyocyte proliferation but loses this potential by postnatal day 7. Stimulating adult cardiomyocytes to reenter the cell cycle remains unclear. Here we show that cardiomyocyte proliferation depends on its metabolic state. Given the connection between the tricarboxylic acid cycle and cell proliferation, we analyzed these metabolites in mouse hearts from postnatal day 0.5 to day 7 and found that α-ketoglutarate ranked highest among the decreased metabolites. Injection of α-ketoglutarate extended the window of cardiomyocyte proliferation during heart development and promoted heart regeneration after myocardial infarction by inducing adult cardiomyocyte proliferation. This was confirmed in Ogdh-siRNA-treated mice with increased α-ketoglutarate levels. Mechanistically, α-ketoglutarate decreases H3K27me3 deposition at the promoters of cell cycle genes in cardiomyocytes. Thus, α-ketoglutarate promotes cardiomyocyte proliferation through JMJD3-dependent demethylation, offering a potential approach for treating myocardial infarction.

Department

Medicine

Link to Full Text

Share

COinS