Epigenetic mechanisms of endothelial dysfunction in type 2 diabetes

Abstract

The development of type-2 diabetes mellitus (T2DM) and its complications is largely due to the complex interaction between genetic factors and environmental influences, mainly dietary habits and lifestyle, which can either accelerate or slow down disease progression. Recent findings suggest the potential involvement of epigenetic mechanisms as a crucial interface between the effects of genetic predisposition and environmental factors. The common denominator of environmental factors promoting T2DM development and progression is that they trigger an inflammatory response, promoting inflammation-mediated insulin resistance and endothelial dysfunction. Proinflammatory stimuli, including hyperglycemia, oxidative stress, and other inflammatory mediators, can affect epigenetic mechanisms, altering the expression of specific genes in target cells without changes in underlying DNA sequences. DNA methylation and post-translational histone modifications (PTHMs) are the most extensively investigated epigenetic mechanisms. Over the past few years, non-coding RNA, including microRNAs (miRNAs), have also emerged as key players in gene expression modulation. MiRNAs can be actively released or shed by cells in the bloodstream and taken up in active form by receiving cells, acting as efficient systemic communication tools. The miRNAs involved in modulation of inflammatory pathways (inflammamiRs), such as miR-146a, and those highly expressed in endothelial lineages and hematopoietic progenitor cells (angiomiRs), such as miR-126, are the most extensively studied circulating miRNAs in T2DM. However, data on circulating miRNA signatures associated with specific diabetic complications are still lacking. Since immune cells and endothelial cells are primarily involved in the vascular complications of T2DM, their relative contribution to circulating miRNA signatures needs to be elucidated. An integrated approach encompassing different epigenetic mechanisms would have the potential to provide new mechanistic insights into the genesis of diabetes and its severe vascular complications and identify a panel of epigenetic markers with diagnostic/prognostic and therapeutic relevance.

Urinary and Blood MicroRNA-126 and -770 are Potential Noninvasive Biomarker Candidates for Diabetic Nephropathy: a Meta-Analysis

“…Interestingly, in contrast to blood miR-126, our meta-analyses showed that urinary miR-126 excretion was significantly increased in patients with DN, although there was a significant heterogeneity. This discrepancy may indicate either a local kidney-specific role or compensatory increases in VEGF and miR-126 in the pathogenesis and/or progression of DN involving microvascular endothelial cells [36, 37]. …”

Clinical relevance of epigenetics in the onset and management of type 2 diabetes mellitus

“…1). 41,42 Activation of the NF-kB pathway, in turn, induces monocytes/ macrophages and endothelial cells production of several cytokines, including TNF-a, IL-1, IL-6, and adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1). 41,42 The association of diabetes, inflammation, and epigenetic changes has been reported also in humans.…”

“…41,42 Activation of the NF-kB pathway, in turn, induces monocytes/ macrophages and endothelial cells production of several cytokines, including TNF-a, IL-1, IL-6, and adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1). 41,42 The association of diabetes, inflammation, and epigenetic changes has been reported also in humans. A recent study on adipose tissue from monozygotic twins discordant for T2DM (diabetics vs. non-diabetics) reported increased expression of inflammatory genes, such as secreted phosphoprotein (SPP)1 (also known as osteopontin, OPN), chemokine (C-C motif) ligand (CCL)18 and IL1RN, in association with variations of global and localized DNA methylation.…”

MiR-507 inhibits the migration and invasion of human breastcancer cells through Flt-1 suppression

“…Promoter hypermethylation of tumour suppressor genes is a kind of epigenetic mechanisms in cancer cells [22]. Epigenetic modifications have been shown to be crucial mediators underlying in miRNA down-regulation and to display a tight correlation with carcinogenesis [16, 23]. Our data demonstrated that the hypermethylation of the upstream promoter of miR-507 led to the down-regulation of miR-507 in breast-cancer tissues and cell lines.…”