Established and Emerging Roles of Epigenetic Regulation in Diabetic Cardiomyopathy

An increasing number of individuals are at high risk of type 2 diabetes (T2DM) and its cardiovascular (CV) complications, which challenges healthcare systems with an increased risk of developing CV diseases. Patients with T2DM exhibit a unique cardiac phenotype termed diabetic cardiomyopathy (DCM). DCM usually involves complex and multifactorial pathogenic drivers, including myocardial inflammation, fibrosis, hypertrophy, and early diastolic dysfunction, which potentially evolve into systolic dysfunction and heart failure. There is a lack of effective treatments for DCM on the basis of the complexity of the disease per se and poor understanding of the mechanisms behind disease development and progression. Despite the considerable research attention on the onset of DCM development and progression, understanding of the full spectrum of pathogenic mechanisms has not yet been fully deciphered. Epigenetic alterations, including DNA methylation, histone modifications, bromodomain extra-terminal (BET)-containing reader proteins, and RNA-based mechanisms (e.g., miRs, lncRNAs, circRNA), are significantly associated with the initiation and evolution of DCM, particularly in the early stage. In this review, we provide insights into the evidence of epigenetic alterations related to DCM development and progression characteristics. Furthermore, the uniqueness of epigenetic changes in DCM in specific cell types within diabetic hearts is discussed. We also review epigenetic cooperation in the context of DCM development and epigenetic biomarkers related to DCM progression. With recent advancements in technology, epitranscriptomics-related to DCM has been uniquely discussed. Finally, this review may provide new avenues for potential implications for future research and the discovery of novel treatment targets for preventing the onset and progression of DCM.