A review on regulation of DNA methylation during post-myocardial infarction

Abstract

Myocardial infarction (MI) imposes a huge medical and economic burden on society, and cardiac repair after MI involves a complex series of processes. Understanding the key mechanisms (such as apoptosis, autophagy, inflammation, and fibrosis) will facilitate further drug development and patient treatment. Presently, a substantial body of evidence suggests that the regulation of epigenetic processes contributes to cardiac repair following MI, with DNA methylation being among the notable epigenetic factors involved. This article will review the research on the mechanism of DNA methylation regulation after MI to provide some insights for future research and development of related drugs.

Keywords: DNA methylation; autophagy; fibrosis; inflammation; myocardial infarction; proliferation.

FIGURE 1

Roles of three DNA methyltransferases Dnmt3a and DNMT3b are responsible for de novo methylation during development by establishing a novel methylation pattern on unmodified DNA. DNMT1 conveys DNA methylation patterns during DNA replication of the newly synthesized daughter strand of the parental strand and plays a role in maintaining post-replicative methylation in cells.

FIGURE 2

Regulation of DNA methylation on inflammation after myocardial infarction (Han, 2019) Rats with MI were administered with 5-Az, resulting in a decrease in the number of M1 phenotype macrophages expressing iNOS and an increase in the level of anti-inflammatory M2 phenotype macrophages. (Zhao et al., 2019). lncRNA KCNQ1OT1 mediated imprinted gene silencing by recruiting DNMT1 and elevating the CpGi methylation level in the promoter region of RUNX3, which in turn suppressed RUNX3 expression levels and affected inflammatory responses through the Notch pathway (Townsend et al., 2022). After MI, the levels of DNA methylation at the SPI1 promoter CpGi were significantly decreased, upregulated SPI1 expression levels bound to the TLR4 promoter and activated the TLR4/NF-κB pathway, exacerbating inflammation.

FIGURE 3

Regulation of DNA methylation on autophagy after myocardial infarction (Han, 2019) ACR binds to DNMT3b and prevents DNA methylation of the Pink1 promoter, which activates the expression of the Pink1, and it mediates FAM65B phosphorylation to inhibit autophagy and cell death (Zhao et al., 2019). Suppressed DNMT3b activity leads to miR-30a hypomethylation and increases its expression, which results in the targeting of the autophagy related gene BECN1 by miR-30a, inhibiting autophagy induction in aging cardiomyocytes (Townsend et al., 2022). DRAM1 was found to be negatively regulated in the rat model of AMI. Regulating the autophagic flow of DRAM1-Atg7-Atg12/Atg5 under the stress condition of myocardial ischemia can alleviate autophagic flow and regulating the mechanism of myocardial cell protection.

FIGURE 4

Regulation of DNA methylation on fibrosis after myocardial infarction HIF-1a plays a role in regulating global DNA hypermethylation and a profibrotic state, potentially through the binding of hypoxia response elements (HRE) to DNMT1 and DNMT3b promoter sites, resulting in a significant increase in DNMT1 and DNMT3b expression levels. Under hypoxic conditions, the profibrotic effect of TGF-β can be inhibited by the 5-Aza, which significantly reduces the expression levels of α-SMA and Col1.

FIGURE 5

The interaction between CPR and DNMT3a inhibits cardiomyocyte proliferation by inhibiting Mcm3. The interaction of CPR with DNMT3a guides DNMT3a to bind CpGi sites of Mcm3 promoter region, directionally elevating methylation levels, thereby reducing Mcm3 expression and inhibiting cardiomyocyte proliferation.