Inhibition of DYRK1A, via histone modification, promotes cardiomyocyte cell cycle activation and cardiac repair after myocardial infarction

Cong Lan, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Department of Cardiology, General Hospital of Western Theater Command, Chengdu, PR China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China.
Caiyu Chen, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China.
Shuang Qu, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China.
Nian Cao, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China; Department of Cardiology, the Sixth Medical Centre, Chinese PLA General Hospital, Beijing, PR China; Department of Internal Medicine, the 519th Hospital of Chinese PLA, Xichang, PR China.
Hao Luo, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China.
Cheng Yu, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China.
Na Wang, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China.
Yuanzheng Xue, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China.
Xuewei Xia, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China.
Chao Fan, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China.
Hongmei Ren, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China.
Yongjian Yang, Department of Cardiology, General Hospital of Western Theater Command, Chengdu, PR China.
Pedro A. Jose, Division of Renal Diseases & Hypertension, Department of Medicine and Department of Physiology/Pharmacology, The George Washington University School of Medicine & Health Sciences, Washington DC, United States.
Zaicheng Xu, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China; Department of Cancer Center, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China. Electronic address: zaichengxu@126.com.
Gengze Wu, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China. Electronic address: wugengze@163.com.
Chunyu Zeng, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China; State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Cardiovascular Research Center of Chongqing College, Department of Cardiology of Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, PR China. Electronic address: chunyuzeng01@163.com.

Document Type

Journal Article

Publication Date

7-7-2022

Journal

EBioMedicine

Volume

82

DOI

10.1016/j.ebiom.2022.104139

Keywords

Cardiac repair; Cardiomyocyte cell cycle activation; DYRK1A; H3K27ac; H3K4me3

Abstract

BACKGROUND: While the adult mammalian heart undergoes only modest renewal through cardiomyocyte proliferation, boosting this process is considered a promising therapeutic strategy to repair cardiac injury. This study explored the role and mechanism of dual-specificity tyrosine regulated kinase 1A (DYRK1A) in regulating cardiomyocyte cell cycle activation and cardiac repair after myocardial infarction (MI). METHODS: DYRK1A-knockout mice and DYRK1A inhibitors were used to investigate the role of DYRK1A in cardiomyocyte cell cycle activation and cardiac repair following MI. Additionally, we explored the underlying mechanisms by combining genome-wide transcriptomic, epigenomic, and proteomic analyses. FINDINGS: In adult mice subjected to MI, both conditional deletion and pharmacological inhibition of DYRK1A induced cardiomyocyte cell cycle activation and cardiac repair with improved cardiac function. Combining genome-wide transcriptomic and epigenomic analyses revealed that DYRK1A knockdown resulted in robust cardiomyocyte cell cycle activation (shown by the enhanced expression of many genes governing cell proliferation) associated with increased deposition of trimethylated histone 3 Lys4 (H3K4me3) and acetylated histone 3 Lys27 (H3K27ac) on the promoter regions of these genes. Mechanistically, via unbiased mass spectrometry, we discovered that WD repeat-containing protein 82 and lysine acetyltransferase 6A were key mediators in the epigenetic modification of H3K4me3 and H3K27ac and subsequent pro-proliferative transcriptome and cardiomyocyte cell cycle activation. INTERPRETATION: Our results reveal a significant role of DYRK1A in cardiac repair and suggest a drug target with translational potential for treating cardiomyopathy. FUNDING: This study was supported in part by grants from the National Natural Science Foundation of China (81930008, 82022005, 82070296, 82102834), National Key R&D Program of China (2018YFC1312700), Program of Innovative Research Team by the National Natural Science Foundation (81721001), and National Institutes of Health (5R01DK039308-31, 7R37HL023081-37, 5P01HL074940-11).

Department

Medicine

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