Oxidative stress and microRNAs in vascular diseases

Abstract

Oxidative stress has been demonstrated to play a causal role in different vascular diseases, such as hypertension, diabetic vasculopathy, hypercholesterolemia and atherosclerosis. Indeed, increased reactive oxygen species (ROS) production is known to impair endothelial and vascular smooth muscle cell functions, contributing to the development of cardiovascular diseases. MicroRNAs (miRNAs) are non-coding RNA molecules that modulate the stability and/or the translational efficiency of target messenger RNAs. They have been shown to be modulated in most biological processes, including in cellular responses to redox imbalance. In particular, miR-200 family members play a crucial role in oxidative-stress dependent endothelial dysfunction, as well as in cardiovascular complications of diabetes and obesity. In addition, different miRNAs, such as miR-210, have been demonstrated to play a key role in mitochondrial metabolism, therefore modulating ROS production and sensitivity. In this review, we will discuss miRNAs modulated by ROS or involved in ROS production, and implicated in vascular diseases in which redox imbalance has a pathogenetic role.

Figure 1

miRNA biogenesis. The pri-miRNA is cleaved to generate a 70–100 nucleotide long hairpin-shaped pre-miRNA by the complex Drosha/DGCR8, in the nucleus. The pre-miRNA is shuttled to the cytoplasm by Exportin 5 and then processed by the ribonuclease III Dicer, to form the mature 22-nt miRNA:miRNA* duplex. Afterwards, one strand of the duplex, the mature single-stranded miRNA, is incorporated into the RISC complex.

Figure 2

(A) miR-200 family role in endothelial dysfunction and in cardiovascular complications linked to diabetes and obesity. This picture summarizes different pathways where a source of ROS or a pathology associated to elevated ROS production (coloured in red) plays a causal role in endothelial or cardiovascular diseases. The tissue or organ district where these mechanisms have been identified are coloured in blue; (B) miR-200 family and NO. Schematic representation of the role played by the free radical NO on miR-200 family induction which leads to ZEB2 downmodulation and Tert upregulation, inducing mES differentiation towards the mesendoderm and cardiovascular lineage.

Figure 3

miR-210 and mitochondrial activity regulation. miR-210 inhibits mitochondrial oxidative phosphorylation inhibiting a series of targets: ISCU1 and ISCU2, participating in the assembly of iron sulfur (FeS)clusters, that, in turn, are present in several electron transport chain and TCA cycle components; COX10, a component of mitochondrial complex I and complex IV; FECH, which is the last enzyme in heme biosynthesis; SDHD, one of the subunits of the inner mitochondrial enzyme succinate dehydrogenase that catalyzes the oxidation of succinate to fumarate during mitochondrial respiration. The inhibition of PHDs by succinate and by GPD1L, which feedback to HIF1A, is also shown.