Inhibition of DYRK1A, via histone modification, promotes cardiomyocyte cell cycle activation and cardiac repair after myocardial infarction
Cong Lan,
Caiyu Chen,
Shuang Qu,
Nian Cao,
Hao Luo,
Cheng Yu,
Na Wang,
Yuanzheng Xue,
Xuewei Xia,
Chao Fan,
Hongmei Ren,
Yongjian Yang,
Pedro A. Jose,
Zaicheng Xu,
Gengze Wu,
Chunyu Zeng
Affiliations
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; Corresponding authors.
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; Corresponding authors.
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; Corresponding authors.
Summary: 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).
