CDK9 binds and activates SGK3 to promote cardiac repair after injury via the GSK-3β/β-catenin pathway

Abstract

The mammalian heart possesses entire regeneration capacity after birth, which is lost in adulthood. The role of the kinase network in myocardial regeneration remains largely elusive. SGK3 (threonine-protein kinase 3) is a functional kinase we identified previously with the capacity to promote cardiomyocyte proliferation and cardiac repair after myocardial infarction. However, the upstream signals regulating SGK3 are still unknown. Based on the quantitative phosphoproteomics data and pulldown assay, we identified cyclin-dependent kinase 9 (CDK9) as a novel therapeutic target in regeneration therapy. The direct combination between CDK9 and SGK3 was further confirmed by co-immunoprecipitation (Co-IP). CDK9 is highly expressed in the newborn period and rarely detected in the adult myocardium. In vitro, the proliferation ratio of primary cardiomyocytes was significantly elevated by CDK9 overexpression while inhibited by CDK9 knockdown. In vivo, inhibition of CDK9 shortened the time window of cardiac regeneration after apical resection (AR) in neonatal mice, while overexpression of CDK9 significantly promoted mature cardiomyocytes (CMs) to re-enter the cell cycle and cardiac repair after myocardial infarction (MI) in adult mice. Mechanistically, CDK9 promoted cardiac repair by directly activating SGK3 and downstream GSK-3β/β-catenin pathway. Consequently, our study indicated that CDK9 might be a novel target for MI therapy by stimulating myocardial regeneration.

Targeting cardiomyocyte cell cycle regulation in heart failure

“…Similarly, overexpression of serine/threonine‐protein kinase 3 (SGK3) or its direct activator CDK9 can promote cardiomyocyte proliferation mainly through inactivating GSK-3β and upregulating β-catenin expression. As new potential therapeutic targets, overexpression of SGK3 or CDK9 after myocardial injury in mouse in vivo promotes cardiac repair and aims to partially restore the cardiac function [ 107 , 166 ]. In addition, low-density lipoprotein receptor-related protein 5 (LRP5) and low-density lipoprotein receptor-related protein 6 (LRP6), co-receptors of Wnt signaling, are key regulators of cardiomyocyte cell cycle activity.…”

Comparative Analysis of Heart Regeneration: Searching for the Key to Heal the Heart—Part II: Molecular Mechanisms of Cardiac Regeneration

“…In addition, the Cyclin-dependent kinases (CDK) family is closely related to cell proliferation. CDK9 expression, the most representative member of the CDK family, declines its levels in the myocardium from newborn to adulthood [ 147 ] ( Figure 3 B). CDK9 is located upstream of the threonine-protein kinase 3 (SGK3), a functional kinase with the capacity to promote CMs proliferation and cardiac repair after MI.…”

“…CDK9 is located upstream of the threonine-protein kinase 3 (SGK3), a functional kinase with the capacity to promote CMs proliferation and cardiac repair after MI. Gain- and loss-of-function studies show that CDK9 promotes cardiac regeneration after apical resection in neonatal mice and its overexpression promotes mature CMs to re-enter the cell cycle, activating SGK3 and the downstream GSK3B/β-catenin pathway [ 147 ]. Moreover, SGK3 promotes β-catenin expression and also upregulates cell cycle genes like Cyclin-D1, c-myc and Cdc20, and downregulates the expression of cell cycle negative regulators such as cyclin kinase inhibitor p21 and cyclin kinase inhibitor p27 [ 148 ] ( Figure 3 B).…”