Novel insights into DNA methylation and its critical implications in diabetic vascular complications

Abstract

Recent epidemiological and clinical studies have shown that type 2 diabetic patients can develop diabetic vascular complications even after intensive glycaemic control. It has been suggested that this phenomenon could be explained by the hypothesis of 'metabolic memory'. The underlying mechanisms between these enduring effects and the prior hyperglycaemic state are still not well understood. Preliminary studies demonstrate that hyperglycaemia can regulate gene expression by epigenetic modifications, such as DNA methylation, which can persistently exist even after glucose normalization. Increasing evidence shows that epigenetic mechanisms may play a substantial role in the pathophysiology of diabetes and its associated vascular complications, including atherosclerosis, diabetic cardiomyopathy (DCM), nephropathy and retinopathy. In this review, we will examine the growing role of DNA methylation in diabetes and its vascular complications, thus it can provide critical implications for the early prevention of diabetes and its vascular complications.

Keywords: Atherosclerosis; DNA methylation; Diabetic cardiomyopathy; Diabetic nephropathy; Diabetic retinopathy; Epigenetics.

Figure 1. Schematic diagram shows the role of epigenetic mechanisms in metabolic memory and diabetic vascular complications

Metabolic memory is the phenomenon of diabetic vascular stresses persisting after glucose normalization in diabetic patients because of early a hyperglycaemic environment. Increasing studies show that epigenetics may be the underlying mechanisms, which can explain metabolic memory. Epigenetic mechanisms including DNA methylation, histone methylation, histone acetylation, are regulated via the action of corresponding DNMTs, HMTs and HATs. In addition, miRNAs can also play a significant role in the process. Together they activate multiple signal transduction pathways and regulated related gene expression, involving blood vessels, heart, kidney and eyes. Then, it can increase the susceptibility of macrovascular complications such as atherosclerosis, DCM and microvascular complications such as nephropathy and retinopathy. ECs, endothelial cells; VSMCs, vascular smooth muscle cells.

Figure 2. Molecular mechanisms of DNA methylation

DNA methylation is exerted by DNMTs at the 5′-position of cytosine residues in CpG dinucleotides (the p denotes the intervening phosphate group) by transferring methyl groups from SAM, thus 5-methylcytosine is formed. DNA methylation of promoter CpG islands generally can regulate gene expression.