| Aims:In mammalian,regenerative therapy after myocardial infarction(MI)is hampered by the limited regenerative capacity of adult heart,while a transient regenerative capacity is maintained in the neonatal heart.Systemic phosphorylation signaling analysis on ischemic neonatal myocardium might be helpful to identify key pathways involved in heart regeneration.We aimed to define kinase-substrate network in ischemic neonatal myocardium and identify key pathways involved in heart regeneration post ischemic insult.Methods: Quantitative phosphoproteomics profiling was performed on infarct border zone of neonatal myocardium at 6 days post-infarction,and kinase-substrate network analysis revealed 58 kinases with enriched substrates and upregulated phosphorylation levels including CHK1 kinase.The effect of CHK1 on cardiac regeneration was tested on ICR-CD1 neonatal and adult mice underwent apical resection or myocardial infarction.Results: CHK1 overexpression promoted neonatal cardiomyocyte proliferation in vivo and vitro.In the neonatal mice,CHK1 knockdown in vivo impaired CM proliferation and regeneration capacity;while in adult mice,the myocardial specific overexpression of CHK1 in the infarct border zone up-regulated the m TORC1/P70S6 K pathway,promoted the translation level of downstream target genes,and finally promoted the proliferation of adult CMs and improved the cardiac function after infarction.Conclusion: Our study indicates that phosphoproteome of neonatal regenerative myocardium could help identify important signaling pathways involved in myocardial regeneration.CHK1 is found to be a key signaling responsible for neonatal regeneration and myocardial overexpression of CHK1 could improve cardiac regeneration in adult hearts through activating m TORC1/P70S6 K pathway,CHK1 might thus serve as a potential novel target in myocardial repair post MI. |
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