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Updated: May 20, 2025
Isolation, Culture and Transduction of Adult Mouse Cardiomyocytes
Published on: August 28, 2016
Foxk1 and Foxk2 promote cardiomyocyte proliferation and heart regeneration
Dongcheng Cai1, Chungeng Liu1,2,3,4, Haotong Li1
1State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China.
Abstract:
Promoting endogenous cardiomyocyte proliferation is a promising strategy for cardiac repair. Identifying key factors that regulate cardiomyocyte proliferation can advance the development of novel therapies for heart regeneration. Here, we identify Foxk1 and Foxk2 as key regulators of cardiomyocyte proliferation, whose expression declines during postnatal heart development. Cardiomyocyte-specific knockout of Foxk1 or Foxk2 impairs neonatal heart regeneration after myocardial infarction (MI) injury. AAV9-mediated Foxk1 or Foxk2 overexpression extends the postnatal cardiomyocyte proliferative window and enhances cardiac repair in adult mice after MI. Mechanistically, Foxk1 and Foxk2 drive cardiomyocyte cell cycle progression by directly activating CCNB1 and CDK1 expression, forming the CCNB1/CDK1 complex that facilitates G2/M transition. Moreover, Foxk1 and Foxk2 promote cardiomyocyte proliferation by upregulating HIF1α expression, which enhances glycolysis and the pentose phosphate pathway (PPP), which further favors cardiomyocyte proliferation. These findings establish Foxk1 and Foxk2 as promising therapeutic targets for cardiac injury.
Insights
Foxk1 and Foxk2 promote heart regeneration by enhancing cardiomyocyte proliferation. Overexpressing these factors improves cardiac repair after myocardial infarction (MI), offering new therapeutic targets for heart injury.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Regenerative Medicine
Background:
- Endogenous cardiomyocyte proliferation is crucial for cardiac repair.
- Identifying regulators of cardiomyocyte proliferation is key for heart regeneration therapies.
- Postnatal heart development involves a decline in cardiomyocyte proliferation.
Purpose of the Study:
- To identify novel regulators of cardiomyocyte proliferation.
- To investigate the role of Foxk1 and Foxk2 in cardiac repair and regeneration.
- To elucidate the molecular mechanisms by which Foxk1 and Foxk2 influence cardiomyocyte cell cycle progression.
Main Methods:
- Cardiomyocyte-specific knockout models of Foxk1 and Foxk2.
- Adeno-associated virus serotype 9 (AAV9) mediated gene delivery for factor overexpression.
- Myocardial infarction (MI) induction in adult mice.
- Analysis of cell cycle markers (CCNB1, CDK1) and metabolic pathways (glycolysis, pentose phosphate pathway).
Main Results:
- Foxk1 and Foxk2 expression declines during postnatal heart development.
- Knockout of Foxk1 or Foxk2 impairs neonatal heart regeneration after MI.
- Overexpression of Foxk1 or Foxk2 extends the cardiomyocyte proliferative window and enhances cardiac repair in adult mice post-MI.
- Foxk1 and Foxk2 directly activate CCNB1 and CDK1, facilitating G2/M cell cycle transition.
- Foxk1 and Foxk2 upregulate HIF1α, enhancing glycolysis and the pentose phosphate pathway (PPP) to promote proliferation.
Conclusions:
- Foxk1 and Foxk2 are critical regulators of cardiomyocyte proliferation and cardiac repair.
- Foxk1 and Foxk2 enhance cardiac regeneration by activating cell cycle progression and specific metabolic pathways.
- Foxk1 and Foxk2 represent promising therapeutic targets for treating cardiac injury and promoting heart regeneration.
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