Abstract 14474: Cdk9-activated Sgk3 Promotes Myocardial Repair and Regeneration After Myocardial Infarction via Gsk-3Å/Å-catenin Pathway

Abstract

Background: Neonatal heart maintains entire regeneration capacity in a transient regeneration window, but the adult heart loses this function. This process involves numberous core hubs dysregulation of expression and activity that adversely affect the myocardium regeneration ability. Present study screened a functional kinase of serine/threonine-protein kinase 3 (SGK3) in cardiac regeneration after neonatal myocardial infarction (MI) using quantitative phosphoproteomics. Methods: We used quantitative phosphoproteomics data of infarct border zone in newborn heart after MI to identify regeneration related kinases. Gain- and loss-of-function experiments were performed to determine the effect of SGK3 in cardiomyocyte (CM) proliferation and cardiac repair after apical resection (AR) or MI. Pull-down assay and co-immunoprecipitation (Co-IP) experiments were conducted to investigate the direct binding target proteins of SGK3. Results: SGK3 protein expression was highly expressed at postnatal day 1 (P1), reduced at postnatal day 7 (P7) until adult. In vitro, CM proliferation ratio was elevated by SGK3 overexpression, while it was decreased by knockdown of SGK3. In vivo, inhibition of SGK3 shortened the time window of cardiac regeneration after AR in neonatal mice, and overexpression of SGK3 significantly promoted CM proliferation and cardiac repair after MI. Mechanistically, SGK3 could be directly combined with and activated by cyclindependent kinase 9 (CDK9). Inhibition of CDK9 partially abolished the effect of SGK3 on CM proliferation. Moreover, SGK3 could repress GSK-3β activity and increase β-catenin expression. Conclusions: Our study revealed a key role of SGK3 in cardiac regeneration following AR or MI injury, which may reopen a novel therapeutic avenue for MI.