Advanced Molecular Research in Cardiology and Treatment Approaches
A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".
Deadline for manuscript submissions: 31 October 2025 | Viewed by 30
Special Issue Editor
Special Issue Information
Dear Colleagues,
Ischemic heart disease remains a leading cause of death worldwide, in part due to the adult heart’s limited regenerative capacity. Two broad approaches have been explored over the last twenty years in the field of cardiac regeneration: (i) the use of stem cells and (ii) the coaxing of endogenous CM to proliferate, both with limited success. Our research investigates the molecular constraints on cardiomyocyte (CM) proliferation after myocardial infarction (MI), focusing on the transcription factor TAp63 and the histone methyltransferase EzH2. We discovered that these two factors form a repressive complex in vivo that silences key mitotic genes in adult CM through coordinated transcriptional and epigenetic mechanisms.
Using both genetic and pharmacological approaches, we show that disrupting TAp63 or EzH2—either by cardiac-specific knockout or gapmer-mediated knockdown—induces robust CM proliferation, restores cell cycle progression, and improves cardiac function post-MI. Mechanistically, we demonstrate that TAp63/EzH2 directly repress genes such as Skp2 and Ect2 by depositing H3K27me3 marks at their promoters. Loss of this repression reactivates mitotic pathways necessary for regeneration. Moreover, we found that the Ras-Raf-Mek-Erk signaling pathway is required for Skp2-mediated p27KIP1 degradation and CM proliferation.
Together, our findings identify the TAp63/EzH2 complex as a key molecular brake on cardiac regeneration. By lifting this brake, we reveal a previously untapped capacity of the adult heart to repair itself through endogenous CM proliferation. These results offer compelling preclinical evidence that targeting TAp63/EzH2 may serve as a viable therapeutic strategy to enhance heart repair after MI.
Dr. Ludger Hauck
Guest Editor
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Keywords
- TAp63
- EzH2
- histone methyltransferase
- cardiomyocyte proliferation
- myocardial infarction
- heart regeneration
- heart repair
- epigenetic regulation
- cardiac regeneration
- Skp2-p27KIP1 pathway
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