Targeting Epigenetic Regulation of Cardiomyocytes through Development for Therapeutic Cardiac Regeneration after Heart Failure

Abstract

Cardiovascular diseases are the leading cause of death globally, with no cure currently. Therefore, there is a dire need to further understand the mechanisms that arise during heart failure. Notoriously, the adult mammalian heart has a very limited ability to regenerate its functional cardiac cells, cardiomyocytes, after injury. However, the neonatal mammalian heart has a window of regeneration that allows for the repair and renewal of cardiomyocytes after injury. This specific timeline has been of interest in the field of cardiovascular and regenerative biology as a potential target for adult cardiomyocyte repair. Recently, many of the neonatal cardiomyocyte regeneration mechanisms have been associated with epigenetic regulation within the heart. This review summarizes the current and most promising epigenetic mechanisms in neonatal cardiomyocyte regeneration, with a specific emphasis on the potential for targeting these mechanisms in adult cardiac models for repair after injury.

miRNAs Epigenetic Tuning of Wall Remodeling in the Early Phase after Myocardial Infarction: A Novel Epidrug Approach

“…This region is in fact modified with the H3K27Me3 mark, associated with chromatin condensation and gene silencing [196]. Also, histone acetylation, as already stated, and CpG island methylation are involved in the silencing of genes that allow the reactivation and proliferation of CMs and could therefore be considered potential therapeutic target to improve the outcomes of MI [197]. The miRNAs presumably involved in the maturation phase mainly regulate cardiomyocyte hypertrophy, vascular smooth muscle cell differentiation, myofibroblast senescence and, more generally, cardiac dysfunction, remodelling and damage (Figure 7 and Table S3).…”

Two decades of heart regeneration research: Cardiomyocyte proliferation and beyond

“…Genetic and epigenetic repression of embryonic cardiomyocyte gene expression during development and maturation may also contribute to the loss of cardiac regenerative capacity (Cui et al, 2018; Kraus, 2022). For example, the transcription factor Meis1 inhibits cardiomyocyte cycling during cardiogenesis by activating the expression of cyclin‐dependent kinase (CDK) inhibitors p15, p16, and p21 potentially contributing to cellcycle arrest in cardiomyocytes in mice (Mahmoud et al, 2013).…”

Cardiomyocyte Ploidy, Metabolic Reprogramming and Heart Repair

“…Accordingly, targeting epigenetic regulators in neonatal CMs, and amplifying them in adult CMs enhance the reparative mechanisms and regenerative capability of the heart. Therefore, the regulation of neonatal epigenetic mechanisms helps to improve CM regeneration in adult injured myocardium [96].…”