Conditional deletion or pharmacological inhibition of DYRK1A induced cardiomyocyte cell cycle activation and improved cardiac function in adult mice subjected to myocardial infarction.
Does DYRK1A inhibition promote cardiomyocyte cell cycle activation and cardiac repair after myocardial infarction in preclinical models?
Inhibition of DYRK1A promotes cardiomyocyte cell cycle reentry and improves cardiac repair following myocardial infarction via epigenetic modifications, suggesting a potential therapeutic target for cardiomyopathy.
p-value: p=<0.001
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).
Lan et al. (Fri,) conducted a other in Myocardial infarction. DYRK1A inhibition (conditional deletion or pharmacological inhibitors such as harmine) vs. Control (wild-type, sham operation, or vehicle) was evaluated on Cardiomyocyte cell cycle activation and cardiac function (LVEF, LVFS) (p=<0.001). Conditional deletion or pharmacological inhibition of DYRK1A induced cardiomyocyte cell cycle activation and improved cardiac function in adult mice subjected to myocardial infarction.