Insights into the Role of Plasmatic and Exosomal microRNAs in Oxidative Stress-Related Metabolic Diseases

Abstract

A common denominator of metabolic diseases, including type 2 diabetes Mellitus, dyslipidemia, and atherosclerosis, are elevated oxidative stress and chronic inflammation. These complex, multi-factorial diseases are caused by the detrimental interaction between the individual genetic background and multiple environmental stimuli. The cells, including the endothelial ones, acquire a preactivated phenotype and metabolic memory, exhibiting increased oxidative stress, inflammatory gene expression, endothelial vascular activation, and prothrombotic events, leading to vascular complications. There are different pathways involved in the pathogenesis of metabolic diseases, and increased knowledge suggests a role of the activation of the NF-kB pathway and NLRP3 inflammasome as key mediators of metabolic inflammation. Epigenetic-wide associated studies provide new insight into the role of microRNAs in the phenomenon of metabolic memory and the development consequences of vessel damage. In this review, we will focus on the microRNAs related to the control of anti-oxidative enzymes, as well as microRNAs related to the control of mitochondrial functions and inflammation. The objective is the search for new therapeutic targets to improve the functioning of mitochondria and reduce oxidative stress and inflammation, despite the acquired metabolic memory.

Keywords: circulating microRNA; endothelial dysfunction; epigenetic; exosomes; inflammation; metabolic diseases; oxidative stress.

Figure 1

Metabolic changes in the endothelial cell. The endogenous increased cytokines act through the Toll-like receptors (TLRs) to activate NF-kB—NLRP3 inflammasome pathway. Under conditions of hyperglycemia, the accumulation of reducing equivalents (NADH+H, FADH2) feeds the respiratory chain with electrons, which leads to greater electron escape and increased superoxide radical (O_2⁻•) production. The increment of polyol pathway leads to Advanced glycation end products (AGEs) accumulation, which act on the AGEs receptors (RAGE), leading to the activation of pro-oxidative enzymes, such as NAD(P)H oxidase, and decrement of NRF2, one important component of the anti-oxidative system of the cell. Increased β-oxidation upon the excess of fatty acid contributes to the accumulation of D-acyl glycerol, thus conducing to the activation of protein kinase C (PKC). The translocation of NF-κB to the nucleus activates the transcription of its target genes, including pro-IL-1, pro-il-18, and Pro-Caspase 1. The activation of NLRP3 inflammasome facilities the cleavage of the pro-Caspase 1 into its active form Caspase1, which in turn transforms IL-1β and IL-18 into their active forms. Subsequently, IL-18 induces the production of TNF-λ, which in turn promotes the synthesis and release of IL-6 and C reactive protein (CRP) (not shown). At the same time, the production of adhesion molecules is activated: vascular adhesion molecule-1 (VCAM-1), platelet-derived grown factor (PDGF), and vascular endothelial grown factor (VEGF). The endoplasmic reticulum (ER) stress contributes to the trigger for NLRP3 inflammasome activation and potentiating oxidative stress.

Figure 2

Some examples of the exosome’s microRNAs’ participation in the pathogenesis of metabolic diseases. Exosomes derived from adipose tissue macrophages, designated ATM-EXO, isolated from obese mice have been shown to confer insulin resistance and glucose intolerance when injected into lean mice (achieved in miR-155). ATM-derived miR-29 can transfer to myocytes, hepatocytes, and adipocytes, causing insulin resistance in vivo. miR-690, abundant in exosomes of anti-inflammatory M2-like macrophages, repolarized ATM-EXO towards an anti-inflammatory M2-like phenotype.