Epigenetics of hypertension as a risk factor for the development of coronary artery disease in type 2 diabetes mellitus

Abstract

Hypertension, a multifaceted cardiovascular disorder influenced by genetic, epigenetic, and environmental factors, poses a significant risk for the development of coronary artery disease (CAD) in individuals with type 2 diabetes mellitus (T2DM). Epigenetic alterations, particularly in histone modifications, DNA methylation, and microRNAs, play a pivotal role in unraveling the complex molecular underpinnings of blood pressure regulation. This review emphasizes the crucial interplay between epigenetic attributes and hypertension, shedding light on the prominence of DNA methylation, both globally and at the gene-specific level, in essential hypertension. Additionally, histone modifications, including acetylation and methylation, emerge as essential epigenetic markers linked to hypertension. Furthermore, microRNAs exert regulatory influence on blood pressure homeostasis, targeting key genes within the aldosterone and renin-angiotensin pathways. Understanding the intricate crosstalk between genetics and epigenetics in hypertension is particularly pertinent in the context of its interaction with T2DM, where hypertension serves as a notable risk factor for the development of CAD. These findings not only contribute to the comprehensive elucidation of essential hypertension but also offer promising avenues for innovative strategies in the prevention and treatment of cardiovascular complications, especially in the context of T2DM.

Keywords: DNA methylation; coronary artery disease; epigenetics; genetic variation; histone; hypertension; modification; type 2 diabetes mellitus.

Figure 1

Epigenetic Modifications: Influence on Chromatin Structure and Gene Expression. DNA, wrapped around nucleosomes, comprises four pairs of histone proteins. Histones are susceptible to various epigenetic modifications, including acetylation, methylation, phosphorylation, sumoylation, and biotinylation. These modifications alter chromatin formation, leading to either an open (active) or closed (inactive) state, thereby modulating transcriptional activity. DNA methylation directly impacts DNA structure, influencing gene transcription. The effect of DNA methylation depends on the specific methylated site. miRNAs primarily target the 3’ UTR of mRNA (though 5’ targeting is possible), leading to the negative regulation of protein production by mRNA degradation or post-transcriptional regulation of mRNA stability.

Figure 2

The biochemical pathways of 5-hydroxymethylcytosine (5hmC) in mammalian DNA. The synthesis of 5hmC is initiated by the TET protein-mediated oxidation (hydroxylation) of 5-methylcytosine (5mC). TET proteins along with co-factors Fe(II) and ascorbate generate 5hmC. Subsequent TET-driven oxidation of 5hmC consistently results in the formation of 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). These oxidized forms are then replaced with cytosine (C) through thymine-DNA glycosylase (TDG)-mediated base excision repair (BER). Additionally, DNA methyltransferases I and III (DNMTs I and III) facilitate the transfer of a methyl group to cytosine, producing 5mC.