Circulating microRNAs as Potential Biomarkers of Endothelial Dysfunction in Obese Children.
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.
Department of Pediatrics, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Chicago, IL.
Abdelnaby
A
Khalyfa
Department of Pediatrics, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Chicago, IL.
Leila
L
Kheirandish-Gozal
Department of Pediatrics, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Chicago, IL.
Rakesh
R
Bhattacharjee
Department of Pediatrics, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Chicago, IL.
Ahamed A
AA
Khalyfa
Department of Pediatrics, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Chicago, IL. Electronic address: dgozal@uchicago.edu.
David
D
Gozal
D029404:Activin Receptors / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000378:metabolism; D004730:Endothelium, Vascular / Q000503:physiopathology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D063990:Gene Ontology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D063766:Pediatric Obesity / Q000378:metabolism* / Q000503:physiopathology; D018121:Receptors, Cytokine / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
D015415:Biomarkers; D001786:Blood Glucose; D016207:Cytokines; D007328:Insulin; C531888:MIRN125 microRNA, human; C546176:MIRN342 microRNA, human; C546819:MIRN365 microRNA, human; D035683:MicroRNAs; D018121:Receptors, Cytokine; D016212:Transforming Growth Factor beta; D002097:C-Reactive Protein; D029404:Activin Receptors
endothelium; microRNA; obesity