Epigenetic regulation in cardiovascular disease: mechanisms and advances in clinical trials

Abstract

Epigenetics is closely related to cardiovascular diseases. Genome-wide linkage and association analyses and candidate gene approaches illustrate the multigenic complexity of cardiovascular disease. Several epigenetic mechanisms, such as DNA methylation, histone modification, and noncoding RNA, which are of importance for cardiovascular disease development and regression. Targeting epigenetic key enzymes, especially the DNA methyltransferases, histone methyltransferases, histone acetylases, histone deacetylases and their regulated target genes, could represent an attractive new route for the diagnosis and treatment of cardiovascular diseases. Herein, we summarize the knowledge on epigenetic history and essential regulatory mechanisms in cardiovascular diseases. Furthermore, we discuss the preclinical studies and drugs that are targeted these epigenetic key enzymes for cardiovascular diseases therapy. Finally, we conclude the clinical trials that are going to target some of these processes.

Fig. 1

DNA methylation regulation. DNA methylation occurs mainly in the islands of cytosinephosphateguanine (CpG) gene promoter region. It promotes gene transcription in the promoter region by activating DNA methyltransferases. DNA methylases can be divided into three categories according to their roles in DNA methylation: writing enzymes, erasing enzymes, and reading enzymes. Writing enzymes catalyze the addition of methyl groups to cytosine residues. The function of erasing enzymes is to modify and remove methyl groups. Reading enzymes can recognize and bind methyl groups to affect gene expression. This figure was created with the aid of Biorender (https://biorender.com/). DNMTs DNA methyltransferases, MBD methyl-CPG-binding domain, ZBTB zinc finger and broad complex, tramtrack, and bric a brac, TET Ten Eleven Translocation, MECP2 methyl-CpG-binding protein 2, UNG uracil–DNA glycosylase

Fig. 2

Histone-modification regulation. Histone modification refers to the process of histone modification such as methylation, acetylation, phosphorylation, adenylation, ubiquitination, and adenosine diphosphate ribosylation under the action of related enzymes. Among them, histone methylation and acetylation are well studied. Histone methyltransferases are mainly involved in the regulation of histone methylation, which transfers methyl groups to histones lysine residues, whereas, histone demethylases have the opposite effect. The methylation action site is on the N atom of the lysine side chain. Histone acetyltransferases are mainly involved in the regulation of histone acetylation, which transfers acetyl groups to histones lysine residues. However, histone deacetylases have the opposite effect. This figure was created with the aid of Biorender (https://biorender.com/). H3K9 histone H3 lysine 9, H3K4 histone H3 lysine 4

Fig. 3

Noncoding RNA regulation. Different mechanisms of action of noncoding RNAs in epigenetic regulations. (1) <50 nt: MicroRNAs (miRNAs): miRNAs complement mRNAs and promote mRNA silencing or degradation. Small interfering RNAs(siRNA): silences gene expression. (2) 50–500 nt: nucleolar small RNA(snoRNA): snoRNA biological function was initially found to modify rRNA. Nuclear small RNA(snRNA): snRNA function is to combine with protein factors to form small nuclear ribonucleoprotein particle and perform the function of splicing mRNA. Transport RNA (tRNA): the main function is to carry amino acids into the ribosome and synthetic proteins with the guidance of mRNA. Ribosomal RNA (rRNA): it binds to proteins to form ribosomes.Its function is to act as a scaffold for mRNA, enabling mRNA molecules to unfold on it to achieve protein synthesis. (3) >500 nt: long noncoding RNAs (lncRNAs): LncRNA acts as mRNA and miRNA endogenous sponges regulating gene expression. Circular RNAs (cirRNAs): circRNA molecules are rich in miRNA-binding sites and act as miRNA sponges in cells, thereby lifting the inhibition of miRNA on target genes and increasing the expression level of target genes. This figure was created with the aid of Biorender (https://biorender.com/)

Fig. 4

Important historical advances of epigenetics in cardiovascular diseases. This figure was created with the aid of Biorender (https://biorender.com/). MCT3 monocarboxylate transporter 3, HDAC histone deacetylase, SAHA suberoylanilide hydroxamic acid, Lp(A) lipoprotein(A), TET2 TET-methylcytidine dioxygenase-2, DOT1L disruptor of telomeric silencing 1-like, NF-kB nuclear transcription factor-kappa B

Fig. 5

Epigenetics-related targets and drugs in atherosclerosis and hypertension. This figure was created with the aid of Biorender (https://biorender.com/). LXRa, liver X receptor a, PPARγ1 peroxisome proliferator-activated receptorγ1, DNMTs DNA methyltransferases, ER estrogen receptor, COL15A1 collagen, type XV, alpha 1, ABCA1 ATP-binding cassette transporter A1 gene, SIRT1 sirtuin1, HDAC histone deacetylase, ICAM-1 intercellular adhesion molecule-1, TLR-4 toll-like receptor-4, vWF von Wilebrand factor, ANGPTL3 angiopoietin-like 3, H3K27me3 trimethylated histone 3 lysine 27, TNF-a tumor necrosis factor (TNF)-a, ACE1 angiotensin-converting enzyme 1

Fig. 6

Epigenetics-related targets and drugs in coronary heart disease and vascular calcification. This figure was created with the aid of Biorender (https://biorender.com/). DNMTs DNA methyltransferases, ER estrogen receptor, COL15A1 collagen, type XV, alpha 1, ABCA1 ATP-binding cassette transporter A1 gene, SIRT1 sirtuin1, HDAC histone deacetylase, ICAM-1 intercellular adhesion molecule-1, TLR-4 toll-like receptor-4, vWF von Wilebrand factor, MMP matrix metalloproteinase

Fig. 7

Epigenetics-related targets and drugs in myocardial infarction and heart failure. This figure was created with the aid of Biorender (https://biorender.com/). FOXO3a forkhead box O3a, AKT-1 protein kinase B-1, TNF-a tumor necrosis factor (TNF)-a, HDAC histone deacetylase, NP natriuretic peptide, HSF1 heat-shock transcription factor 1, SIRT1 sirtuin1, COX-2 cyclooxygenase-2, PCSK9 proprotein convertase subtilisin-kexin type 9, IL-6 interleukin 6, VEGF vascular endothelial growth factor, eNOS endothelial nitric oxide synthase, ANG-1 angiopoietin-1, ANP atrial natriuretic peptide, BNP brain natriuretic peptide, STAT3 signal transducer and activator of transcription 3, β-SMA β-smooth muscle actin