Diabetes is the most common metabolic disorder and is recognized as one of the most important health threats of our time. MicroRNAs (miRNAs) are a novel group of non-coding small RNAs that have been implicated in a variety of physiological processes, including glucose homeostasis. Recent research has suggested that miRNAs play a critical role in the pathogenesis of diabetes and its related cardiovascular complications. This review focuses on the aberrant expression of miRNAs in diabetes and examines their role in the pathogenesis of endothelial dysfunction, cardiovascular disease, and diabetic retinopathy. Furthermore, we discuss the potential role of miRNAs as blood biomarkers and examine the potential of therapeutic interventions targeting miRNAs in diabetes.

Chronic kidney disease (CKD) is a global health burden and is independently associated with increased cardiovascular disease risk. Assessment of cardiovascular risk in the general population using prognostic models based on routinely collected risk factors is embedded in clinical practice. In CKD, prognostic models may misrepresent risk due to the interplay of traditional atherosclerotic and non-traditional risk factors. This systematic review’s aim was to identify routinely collected risk factors for inclusion in a CKD-specific cardiovascular prognostic model. Systematic review and meta-analysis of observational cohort studies and randomized controlled trials. Studies identified from MEDLINE and Embase searches using a pre-defined and registered protocol (PROSPERO ID—2016:CRD42016036187). The main inclusion criteria were individuals ≥18 years of age with non-endstage CKD. Routinely collected risk factors where multi-variable adjustment for established cardiovascular risk factors had occurred were extracted. The primary outcome was fatal and non-fatal cardiovascular events. The review of 3,232, abstracts identified 29 routinely collected risk factors of which 20 were presented in more than 1 cohort. 21 cohorts were identified in relation to 27,465 individuals and 100,838 person-years. In addition to established traditional general population cardiovascular risk factors, left ventricular hypertrophy, serum albumin, phosphate, urate and hemoglobin were all found to be statistically significant in their association with future cardiovascular events. These non-traditional risk factors should be assessed in the development of future cardiovascular prognostic models for use in individuals with CKD.

Rationale:: Circulating proangiogenic cells (PACs) support postischemic neovascularization. Cardiovascular disease and diabetes mellitus impair PAC regenerative capacities via molecular mechanisms that are not fully known. We hypothesize a role for microRNAs (miRs). Circulating miRs are currently investigated as potential diagnostic and prognostic biomarkers. Objective:: The objectives were the following: (1) to profile miR expression in PACs from critical limb ischemia (CLI) patients; (2) to demonstrate that miR-15a and miR-16 regulate PAC functions; and (3) to characterize circulating miR-15a and miR-16 and to investigate their potential biomarker value. Methods and Results:: Twenty-eight miRs potentially able to modulate angiogenesis were measured in PACs from CLI patients with and without diabetes mellitus and controls. miR-15a and miR-16 were further analyzed. CLI-PACs expressed higher level of mature miR-15a and miR-16 and of the primary transcript pri–miR-15a/16-1. miR-15a/16 overexpression impaired healthy PAC survival and migration. Conversely, miR-15a/16 inhibition improved CLI-PAC–defective migration. Vascular endothelial growth factor-A and AKT-3 were validated as direct targets of the 2 miRs, and their protein levels were reduced in miR-15a/16–overexpressing healthy PACs and in CLI-PACs. Transplantation of healthy PACs ex vivo–engineered with anti–miR-15a/16 improved postischemic blood flow recovery and muscular arteriole density in immunodeficient mice. miR-15a and miR-16 were present in human blood, including conjugated to argonaute-2 and in exosomes. Both miRs were increased in the serum of CLI patients and positively correlated with amputation after restenosis at 12 months postrevascularization of CLI type 2 diabetes mellitus patients. Serum miR-15a additionally correlated with restenosis at follow-up. Conclusions:: Ex vivo miR-15a/16 inhibition enhances PAC therapeutic potential, and circulating miR-15a and miR-16 deserves further investigation as a prognostic biomarker in CLI patients undergoing revascularization.

The pericardial fluid (PF) is contained in the pericardial sac surrounding the heart. MicroRNA (miRNA) exchange via exosomes (endogenous nanoparticles) contributes to cell-to-cell communication. We investigated the hypotheses that the PF is enriched with miRNAs secreted by the heart and that it mediates vascular responses through exosome exchange of miRNAs. The study was developed using leftover material from aortic valve surgery. We found that in comparison with peripheral plasma, the PF contains exosomes enriched with miRNAs co-expressed in patients' myocardium and vasculature. At a functional level, PF exosomes improved survival, proliferation, and networking of cultured endothelial cells (ECs) and restored the angiogenic capacity of ECs depleted (via Dicer silencing) of their endogenous miRNA content. Moreover, PF exosomes improved post-ischemic blood flow recovery and angiogenesis in mice. Mechanistically, (1) let-7b-5p is proangiogenic and inhibits its target gene, TGFBR1, in ECs; (2) PF exosomes transfer a functional let-7b-5p to ECs, thus reducing their TGFBR1 expression; and (3) let-7b-5p depletion in PF exosomes impairs the angiogenic response to these nanoparticles. Collectively, our data support the concept that PF exosomes orchestrate vascular repair via miRNA transfer.

The communication between vascular endothelial cells (ECs) and pericytes in the microvasculature is fundamental for vascular growth and homeostasis; however, these processes are disrupted by diabetes. Here we show that modulation of p75^NTRexpression in ECs exposed to high glucose activates transcription of miR-503, which negatively affects pericyte function. p75^NTRactivates NF-κB to bind the miR-503 promoter and upregulate miR-503 expression in ECs. NF-κB further induces activation of Rho kinase and shedding of endothelial microparticles carrying miR-503, which transfer miR-503 from ECs to vascular pericytes. The integrin-mediated uptake of miR-503 in the recipient pericytes reduces expression ofEFNB2andVEGFA, resulting in impaired migration and proliferation. We confirm operation of the above mechanisms in mouse models of diabetes, in which EC-derived miR-503 reduces pericyte coverage of capillaries, increased permeability and impaired post-ischaemic angiogenesis in limb muscles. Collectively, our data demonstrate that miR-503 regulates pericyte–endothelial crosstalk in microvascular diabetic complications.