Extracellular microRNAs and endothelial hyperglycaemic memory: a therapeutic opportunity?

Abstract

Type 2 diabetes mellitus (T2DM) is a major cause of cardiovascular (CV) disease. Several large clinical trials have shown that the risk for patients with diabetes of developing CV complications is only partially reduced by early, intensive glycaemic control and lifestyle interventions, and that such complications result from changes in complex, not fully explored networks that contribute to the maintenance of endothelial function. The accumulation of senescent cells and the low-grade, systemic, inflammatory status that accompanies aging (inflammaging) are involved in the development of endothelial dysfunction. Such phenomena are modulated by epigenetic mechanisms, including microRNAs (miRNAs). MiRNAs can modulate virtually all gene transcripts. They can be secreted by living cells and taken up in active form by recipient cells, providing a new communication tool between tissues and organs. MiRNA deregulation has been associated with the development and progression of a number of age-related diseases, including the enduring gene expression changes seen in patients with diabetes. We review recent evidence on miRNA changes in T2DM, focusing on the ability of diabetes-associated miRNAs to modulate endothelial function, inflammaging and cellular senescence. We also discuss the hypothesis that miRNA-containing extracellular vesicles (i.e. exosomes and microvesicles) could be harnessed to restore a 'physiological' signature capable of preventing or delaying the harmful systemic effects of T2DM.

Keywords: antidiabetic drug; cardiovascular disease; diabetes complications; extracellular vesicles, exosomes; glycaemic control; metabolic memory; metformin; microRNAs; type 2 diabetes.

Figure 1

Pleiotropic effects of hyperglycaemia‐induced miR‐126 underexpression and insulin resistance. Hyperglycaemia‐induced underexpression of miR‐126 may have favourable effects on adipose cells and hepatocytes in patients with insulin resistance, because miR‐126 downregulates insulin receptor substrate (IRS)‐1, the key gene signalling insulin activation (a). Reduced miR‐126 levels in such a setting could thus increase cell survival chances; however, hyperglycaemia‐induced miR‐126 underexpression can exert harmful effects on EC, inducing upregulation of SPRED1 and PIK3R2, two of the most effective angiogenic pathway inhibitors (b). In turn, endothelial dysfunction promotes development of diabetic complications.

Figure 2

Epigenetic damage transmission. Postulated mechanism. Extracellular vesicles (EVs) contain mRNAs, microRNAs (miRNAs) and other non‐coding RNAs, as well as a number of proteins. EVs can be transferred to recipient cells, where shuttled RNA can be functional. The endothelium uses EVs for physiological cell–cell communication (a). Hyperglycaemia can exert semi‐permanent epigenetic damage in endothelial cells (b). The resulting EVs may have an altered content capable of propagating an ‘incorrect’ signature that modifies the epigenetic set‐up in receiving cells even after stimulus removal; this would perpetuate the insult despite glucose normalization (c), which can be achieved through hypoglycaemic medications and/or lifestyle interventions.