Can Epigenetics of Endothelial Dysfunction Represent the Key to Precision Medicine in Type 2 Diabetes Mellitus?

Abstract

In both developing and industrialized Countries, the growing prevalence of Type 2 Diabetes Mellitus (T2DM) and the severity of its related complications make T2DM one of the most challenging metabolic diseases worldwide. The close relationship between genetic and environmental factors suggests that eating habits and unhealthy lifestyles may significantly affect metabolic pathways, resulting in dynamic modifications of chromatin-associated proteins and homeostatic transcriptional responses involved in the progression of T2DM. Epigenetic mechanisms may be implicated in the complex processes linking environmental factors to genetic predisposition to metabolic disturbances, leading to obesity and type 2 diabetes mellitus (T2DM). Endothelial dysfunction represents an earlier marker and an important player in the development of this disease. Dysregulation of the endothelial ability to produce and release vasoactive mediators is recognized as the initial feature of impaired vascular activity under obesity and other insulin resistance conditions and undoubtedly concurs to the accelerated progression of atherosclerotic lesions and overall cardiovascular risk in T2DM patients. This review aims to summarize the most current knowledge regarding the involvement of epigenetic changes associated with endothelial dysfunction in T2DM, in order to identify potential targets that might contribute to pursuing "precision medicine" in the context of diabetic illness.

Keywords: antidiabetic drugs; endothelial dysfunction; epigenetic changes; type 2 diabetes.

Figure 1

Simplified overview of main epigenetic modifications. (A). Chromosomal DNA is packaged around histone proteins to form nucleosomes. Nucleosome opening and accessibility to nuclear factors is regulated, in part, by post-translational modifications of histone tails that include phosphorylation, ubiquitination, acetylation and methylation. Acetylation reactions on lysine (K) residues by histone acetyl-transferase (HAT) mask the positive charges of the aminoacidic side chains and thus allow chromatin to assume a less condensed conformation permissive for transcription. In contrast, deacetylation reactions by histone deacetylase (HDAC), increasing the chromatin packaging, prevent DNA transcription. (B). DNA methylation consists of adding a methyl group to the carbon-5 position of a cytosine in the so-called CG Islands by DNA-methyltransferase (DNMT) enzymes. The methylation of CpG islands may induce gene silencing by preventing the binding of transcription factors (TFs) to the promoter or favouring the binding of proteins endowed with a methylated CpG (MeCpG Binding-Protein). DNA methylation promotes the persistence of certain histone states, such as deacetylation, thus providing a mechanism for perpetuating post-translational histone modifications. (C). Non-coding (nc) RNAs are conventionally grouped into small ncRNAs and long ncRNAs. According to their function, ncRNAs can be classified in constitutively expressed housekeeping molecules and regulatory molecules such as micro (miRNA) and long non coding (lncRNAs) RNAs. Among these molecules, miRNAs are the most extensively studied and represent the principal epigenetic regulators of gene expression, acting predominantly at the post-transcriptional level.

Figure 2

Epigenetic changes in T2DM-related endothelial dysfunction. Schematic examples of hyperglycaemia-associated histone modifications in endothelium, with subsequent upregulated expression of pro-inflammatory signalling pathways and representative angiogenesis-associated miRNAs (angioMiRs), inflammation-associated miRNAs (inflammaMiRs) and senescence-associated miRNAs (seneMiRs) whose levels are deregulated under diabetes. Advances in understanding the mechanisms involved in reversible epigenetic changes will hopefully help to identify epigenetic biomarkers and novel therapeutic targets for additional interventions that can delay the harmful effects of diabetes on endothelial function.