MicroRNAs as regulators of endothelial cell functions in cardiometabolic diseases

Abstract

Endothelial cells (ECs) provide nutrients and oxygen essential for tissue homeostasis. Metabolic imbalances and other environmental stimuli, like cytokines or low shear stress, trigger endothelial inflammation, increase permeability, compromise vascular tone, promote cell proliferation, and ultimately cause cell death. These factors contribute to EC dysfunction, which is crucial in the development of cardiometabolic diseases. microRNAs (miRNAs) are small non-coding RNAs that have important functions in the regulation of ECs. In the present review, we discuss the role of miRNAs in various aspects of EC pathology in cardiometabolic diseases like atherosclerosis, type 2 diabetes, obesity, and the metabolic syndrome, and in complication of those pathologies, like ischemia. We also discuss the potential therapeutic applications of miRNAs in promoting angiogenesis and neovascularization in tissues where the endothelium is damaged in different cardiometabolic diseases. This article is part of a Special Issue entitled: MicroRNAs and lipid/energy metabolism and related diseases edited by Carlos Fernández-Hernando and Yajaira Suárez.

Keywords: Atherosclerosis; Cardiovascular disease; Endothelial cells; Metabolic syndrome; MicroRNAs; Type 2 diabetes.

Figure 1. microRNAs affect the functions of ECs in atherosclerosis

A. In unbranched arteries, ECs are subject to laminar flow and high shear stress. In atheroprone sites, where curvatures and arterial bifurcations permanently perturb the blood flow, ECs are exposed to low shear stress. This causes EC dysfunction and promotes the development of atherosclerotic lesions, where leukocytes infiltrate in the subendothelial space, secrete cytokines, and LDLs are oxidized, further promoting the inflammatory microenvironment. Most of the cues that favor EC dysfunction also affect the expression of specific miRNAs, which can either exacerbate or improve the phenotype of ECs. B. Laminar flow-induced miRNAs: miRNAs -10a, -30-5p, -23b, -27b, -19a, and -126-5p are induced in high shear stress in areas of laminar flow and through the action of their targets, they overall decrease inflammation, inhibit proliferation by blocking the cell cycle and promote the proliferative potential. C. Disturbed flow-induced miRNAs: miRNAs -21, -92a, -712/205, -34 are induced in disturbed flow and promote inflammation. On the other hand, miR-663 is induced in low shear stress, but it inhibits inflammation through the action of unknown targets. D. Ox-LDL is responsible for the upregulation of miR-365, while it downregulates let-7g. Overall the regulation of these miRNAs contributes to reduce inflammation, apoptosis and inhibit senescence in ECs. E. Inflammatory cytokine-induced miRNAs: TNFα induces the expression of miR-31, miR-17-3p, miR-155, while it decreases the expression of miR-181b; IL1β increases miR-146a/b, while IL3 in conjunction with bFGF induces the expression of miR-222. The combined action of cytokine-induced miRNAs is to reduce inflammation, vascular relaxation and inhibit the proliferation of ECs.

Figure 2. Endothelial cell dysfunction in diabetes

A. Hyperglycemia and other pathological insults resulting from the metabolic syndrome can cause EC dysfunction. Often, diabetic patients have insufficient vasodilation, which can result in ischemia. Complications from atherosclerosis, like atherothrombotic clots, can block capillaries and further enhance ischemia in peripheral areas. miRNAs have been shown to be interesting targets to prevent endothelial dysfunction associated with complications of diabetes and the metabolic syndrome. B. miRNAs can modulate vascular tone. miR-155 and miR-125a/b can promote and reduce vasorelaxation, respectively. C. High glucose levels similar to the ones found in diabetic patients can modulate the expression of several miRNAs, like miRNAs -503, -200b, -155, -146a, -1, which overall promote inflammation, decrease proliferation and induce vasoconstriction, therefore worsening EC dysfunction. D. Oxidative agents, like hydrogen peroxide, can induce the expression of miRNAs, like miR-200c, which promote apoptosis, growth arrest and senescence. E. In ischemia, several miRNAs are upregulated by the low oxygen tension, or hypoxia. MiR-210 and miR-424 are induced and promote neovascularization by targeting EFNA3 and CUL2, respectively. Other miRNAs can be potential targets for neovascularization in ischemia, like miR-19a and miR-92a, which impair neovascularization, or miR-126-5a, which favors angiogenesis.