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Phosphoproteomic Analysis of Neonatal Regenerative Myocardium Revealed Important Roles of CHK1 via Activating mTORC1/P70S6K Pathway Reappraisal of Reported Genes for Sudden Arrhythmic Death: An Evidence-Based Evaluation of Gene Validity for Brugada Syndrome Effect of Pre-Hospital Crushed Prasugrel Tablets in Patients with STEMI Planned for Primary Percutaneous Coronary Intervention: The Randomized COMPARE CRUSH Trial High-Sensitivity Troponin and The Application of Risk Stratification Thresholds in Patients with Suspected Acute Coronary Syndrome Heart Failure With Preserved, Borderline, and Reduced Ejection Fraction: 5-Year Outcomes Ticagrelor versus Clopidogrel in Patients with STEMI Treated with Fibrinolytic Therapy: TREAT Trial From Nonclinical Research to Clinical Trials and Patient-registries: Challenges and Opportunities in Biomedical Research Global, regional, and national age-sex specific mortality for 264 causes of death, 1980–2016: a systematic analysis for the Global Burden of Disease Study 2016
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Original ResearchFebruary 26, 2020

JOURNAL：Circulation. Article Link

Phosphoproteomic Analysis of Neonatal Regenerative Myocardium Revealed Important Roles of CHK1 via Activating mTORC1/P70S6K Pathway

Y Fan, XJ Guo, LS Wang et al. Keywords: regenerative myocardium

ABSTRACT

BACKGROUND - 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, and kinase-substrate network analysis revealed 11 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 MI.

 

RESULTS - In vitro, CHK1 overexpression promoted, while CHK1 knockdown blunted cardiomyocyte (CM) proliferation. In vivo, inhibition of CHK1 hindered myocardial regeneration on resection border zone in neonatal mice. In adult MI mice, CHK1 overexpression on infarct border zone upregulated mTORC1/P70S6K pathway, promoted CM proliferation and improved cardiac function. Inhibiting mTOR activity by rapamycin blunted the neonatal CM proliferation induced by CHK1 overexpression in vitro.

 

CONCLUSIONS - 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. Myocardial overexpression of CHK1 could improve cardiac regeneration in adult hearts through activating mTORC1/P70S6K pathway, CHK1 might thus serve as a potential novel target in myocardial repair post MI.

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