Here is the information focusing on miRNAs as biomarkers in the pediatric population with an emphasis on cardiovascular diseases.
MicroRNAs (miRNAs, miRs) are abundant small noncoding RNAs that function post-transcriptionally by negatively regulating the expression of messenger RNAs (mRNAs) via transcript degradation or translational repression. miRNAs modulate gene expression by targeting reverse complementary 6–8 nucleotide “seed” sequences, most frequently located within the 3′ untranslated regions (3′UTR) of mRNAs.
As a vital component of gene regulation, miRNAs can target the expression of a wide variety of genes in various cell and tissue types, and it is estimated that more than 60% of the human genome is subject to their regulation.
A number of different miRNAs are expressed in different cell and tissue types, and multiple roles for miRNAs in the regulation of various biological and disease processes have recently been elucidated.
Additionally, while many miRNAs are located within cells, miRNAs are also often found in the extracellular environment. Cell-free or circulating miRNAs have been stably detected in both plasma and serum, and studies have shown that these extracellular miRNAs exist not only through cell lysis, but also via active secretion.
The integrity and stability of endogenous circulating miRNAs can be explained via their interaction with and/or packaging within other secretory particles, protecting them from ribonuclease degradation.
Argonaute-2 (Ago-2), a key effector protein, for example, has been shown to be a miRNA carrier in peripheral blood, and high-density lipoproteins (HDLs) have been shown to participate in the transport and delivery of miRNAs in human plasma. Moreover, circulating miRNAs can be stably transported within extracellular vesicles, including inside apoptotic bodies, microvesicles and exosomes. In particular, vesicles such as exosomes have important roles in cell to cell communication, and miRNAs, along with other cargo, can be selectively packaged and transported specifically to recipient cells.
Pathophysiologic changes in the progression to heart failure often occur prior to the clinical presentation of symptoms, however, many existing biomarkers for these pathologic changes have not been validated in children. Thus, it remains critical for new clinical biomarkers in pediatric heart failure patients to focus on: better understanding the pathophysiology of the disease, informing treatment decisions, and/or predicting outcomes.
Importantly, diagnostic and prognostic miRNA disease biomarkers can lead to the early subclinical detection of cardiotoxic or pathological changes, which can lead to early intervention, and in some cases to a reversal of pathologic changes. While pediatric specific biomarker studies relevant to clinical cardiology remain limited, over the past several years, a number of promising pediatric studies have been conducted.
Recent studies have also investigated circulating miRNA levels in association with congenital heart defects. Ramachandran et al. showed an inverse correlation between the levels of miR-129-5p in circulating microvesicles of patients with single ventricle physiology, and the likelihood these patients will eventually develop heart failure.
Another study showed that differential expression of four miRNAs (miRNAs-19b, miR-22, miR29c and miR-375) in the serum of pregnant women were highly predictive of the presence of fetal congenital heart defects.
Interestingly, miR-29 (29b) and miR-499 expression was elevated in patients with cardiomyocyte injury post anthracycline treatment, suggesting circulating miR-29 is associated with cardiac defect/injury.
Similarly, miR-499, miR208a and miR-208b (the so called MyomiRs due to their co-localization with muscle-specific genes) expression was highly up-regulated in pediatric patients post open heart surgery, and their expression was associated with delayed recovery and/or known markers of cardiac injury . Although the number of patients used in these studies is relatively small, the common dysregulation of these miRNAs support their association with cardiac-related congenital defects.
The growing childhood obesity epidemic contributes to increased morbidity and mortality in young patients, with a particularly increased risk of developing atherosclerosis, endothelial dysfunction, hypertension, and metabolic syndrome, which ultimately contribute to significant increases in cardiovascular dysfunction.
Importantly, miR-125a-5p, miR-342-3p, and miR-365b-3p, have been identified as potential diagnostic biomarkers of endothelial dysfunction in pediatric patients, and their common predicted mRNA target genes are involved in transforming growth factor-β signaling, cytokine-cytokine receptor interactions, and activin receptor-like kinase in cardiac myocytes, suggesting plasma miRNAs may be useful screening tools for the presence of endothelial dysfunction in children prior to the onset of cardiovascular complications.
More recently, Circulating miR-663 was shown as a useful classifier for vascular responsiveness to acute oxygen and inhaled nitrous oxide challenges in pediatric pulmonary arterial hypertension (PAH) subjects, suggesting that circulating miRNAs correlate with vascular function in these patients
Future studies and increased patient numbers will likely find ways to mitigate these problems as the miRNA biomarker field continues to grow.
C.C. Sucharov et al. Progress in Pediatric Cardiology 49 (2018) 50–52
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