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Original Research: Pediatrics |

Circulating microRNAs as Potential Biomarkers of Endothelial Dysfunction in Obese Children

Abdelnaby Khalyfa, PhD; Leila Kheirandish-Gozal, MD; Rakesh Bhattacharjee, MD; Ahamed A. Khalyfa, BSc; David Gozal, MD, FCCP
Author and Funding Information

FUNDING/SUPPORT: This work is supported by the National Institutes of Health [Grant HL-65270 to D. G. and L. K.-G.], the Herbert T. Abelson Endowed Chair in Pediatrics, and the American Heart Association [Grant 13SDG14780079 to R. B.].

CORRESPONDENCE TO: David Gozal, MD, FCCP, Department of Pediatrics, University of Chicago, KCBD, Room 4100, 900 E. 57th St, Mailbox 4, Chicago, IL 60637


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;149(3):786-800. doi:10.1378/chest.15-0799
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Background  Cardiovascular disease (CVD) is a complex disease with multifactorial etiology. The presence of endothelial dysfunction constitutes an early risk factor for CVD in children. Circulating microRNAs (miRNAs) are small noncoding RNAs that regulate gene expression and represent a novel class of biomarkers and therapeutic targets; therefore, we examined whether the presence of endothelial dysfunction is associated with differential expression of plasma miRNAs in otherwise healthy children.

Methods  A total of 70 children (aged 5-10 years) were recruited and classified into two groups (normal endothelial function [NEF] and endothelial dysfunction). Time to peak postocclusive reperfusion (Tmax) was considered as the indicator of either normal endothelial function (NEF; Tmax < 45 s) or endothelial dysfunction (Tmax ≥ 45 s). Lipid profiles, high-sensitivity C-reactive protein, fasting glucose, and insulin were assayed using enzyme-linked immunosorbent assay. miRNAs isolated from plasma were assayed with a custom human CVD array, followed by quantitative polymerase chain reaction verification of candidates. In addition, bioinformatics approaches including combinatorial target prediction algorithms and gene ontology were applied.

Results  Three miRNAs that have been previously linked to cardiomyopathy, hsa-miR-125a-5p, hsa-miR-342-3p, and hsa-miR-365b-3p, were identified as potential biomarkers of children with endothelial dysfunction. The miRNA predicted gene targets revealed 31 common targets among all three putative candidate biomarker miRNAs and encompass three biologic pathways, including transforming growth factor-β signaling, cytokine-cytokine receptor interactions, and activin receptor-like kinase in cardiac myocytes.

Conclusions  Plasma miRNAs may be useful as potential screening tools for the presence of endothelial dysfunction in children and may reveal endothelial dysfunction-relevant target genes.

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