Epigenetic Mechanisms in Heart Diseases

Abstract

Heart diseases (HDs) continue to be among the major diseases that adversely affect human health worldwide, with complex interactions between genetic, environmental, and biochemical factors contributing to their progression. These include coronary heart disease, hypertension, heart failure, vascular calcification, etc. Cardiovascular diseases have been extensively studied in the Framingham Heart Study since 1948, spanning three generations over the past 70 years, and are highly correlated with various factors, including biochemical, environmental, behavioral, and genetic factors. In recent years, epigenetic mechanisms have emerged as crucial regulators of cardiovascular pathology, influencing gene expression without altering the underlying DNA sequence. Moreover, early detection and diagnosis of heart diseases are crucial for improving treatment and prognosis. Recent studies on heart disease have found that the expression of potential candidate genes related to the disease is associated with epigenetic mechanisms. Indeed, abnormal methylation states have been detected in candidate genes that can serve as biomarkers to assess the progression of heart disease. Recent advances in next-generation sequencing techniques have contributed significantly to our understanding of heart diseases, including the role of DNA methylation, adenosine triphosphate (ATP)-dependent chromatin conformation and remodeling, post-translational modifications of histones and non-coding RNAs. Lastly, this review examines the latest discoveries in the epigenetic regulation of heart diseases, highlighting the roles of DNA methyltransferases (DNMTs), histone deacetylases (HDACs), sirtuins (SIRTs), and ten-eleven translocation proteins (TETs). Additionally, this review highlights preclinical therapeutic strategies targeting epigenetic modifiers, offering new avenues for precision medicine in cardiology. Understanding these epigenetic pathways is crucial for developing novel biomarkers and epigenetic-based therapies that aim to reverse maladaptive cardiac remodeling and enhance clinical outcomes.

Keywords: DNMTs; HDACs; SIRTs; TETs; drugs; epigenetics; heart diseases; microRNAs; non-coding RNAs.

Fig. 1.

Historical timeline of epigenetics and the development of epigenetic drugs. 5mc, 5-methylcytosine; CTCF, CCCTC-binding factor; NIH, National Institutes of Health; FDA, Food and Drug Administration; EZH2, Enhancer of Zeste Homolog 2; LSD1, Lysine-Specific Demethylase 1; TET, ten-eleven translocation; DNMT, DNA methyltransferase; HDAC, histone deacetylase.

Fig. 2.

Members of the DNMT family possess a common catalytic domain in their structural composition. DNMT, DNA methyltransferase; DAMP, DNMT1-Associated Maintenance Protein; PCNA, Proliferating Cell Nuclear Antigen; NLS, Nuclear Localization Signal; RFTS, Replication Foci Targeting Sequence; CXXC, Cysteine-X-X-Cysteine; AIL, Autoinhibitory Linker; BAH, Bromo-Adjacent Homology; (GK)_n, Glycine Lysine Repeats; PWWP, Pro-Trp-Trp-Pro; ADD, ATRX-DNMT3-DNMT3L; MTase, Methyltransferase.

Fig. 3.

The structural composition of the TETs is defined by the presence of one core catalytic domain at the C-terminal. The CXXC domain is located at the N-terminal of TET1 and TET3, which facilitates direct DNA binding, whereas TET2 does not possess this domain. TET, ten-eleven translocation; CXXC, Cysteine-X-X-Cysteine; DSBH, Double-Stranded $\beta$-Helix; NCLC, N-terminal Cysteine-rich.

Fig. 4.

Classifications of the histone deacetylase family and domains that characterize the different members of each HDAC subfamily. HDAC, Histone deacetylase; SIRT, Sirtuin.

Fig. 5.

The role of epigenetic factors, such as writers, erasers, and readers, is pivotal in the realm of cardiac physiology. I/R, ischemia/reperfusion.

Fig. 6.

The regulation of microRNAs (miRNAs) in cardiac tissue is instrumental in the prevention of heart diseases.

Fig. 7.

Potential epigenetic-related drugs in heart diseases. SNHG12, Small Nucleolar RNA Host Gene 12; SAHA, Suberoylanilide Hydroxamic Acid; NaPB, Sodium Phenylbutyrate; MIAT, Myocardial Infarction–Associated Transcript; BET, Bromodomain and Extra-Terminal; SGLT2, Sodium-Glucose Cotransporter 2; circ-FOXO3, Circular Forkhead box O3.