MicroRNA dysregulation in lung injury: the role of the miR-26a/EphA2 axis in regulation of endothelial permeability

MicroRNAs (miRNAs) are noncoding RNAs that regulate gene expression in many diseases, although the contribution of miRNAs to the pathophysiology of lung injury remains obscure. We hypothesized that dysregulation of miRNA expression drives the changes in key genes implicated in the development of lun...

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Published in:American journal of physiology. Lung cellular and molecular physiology 2018-10, Vol.315 (4), p.L584-L594
Main Authors: Good, Ryan J, Hernandez-Lagunas, Laura, Allawzi, Ayed, Maltzahn, Joanne K, Vohwinkel, Christine U, Upadhyay, Arun K, Kompella, Uday B, Birukov, Konstantin G, Carpenter, Todd C, Sucharov, Carmen C, Nozik-Grayck, Eva
Format: Article
Language:English
Subjects:
Animals
Antibiotics, Antineoplastic - toxicity
Bleomycin
Bleomycin - toxicity
Cadherins
Cell adhesion
Cell Membrane Permeability
Cells, Cultured
Endothelial cells
Endothelium
Endothelium, Vascular - drug effects
Endothelium, Vascular - metabolism
Endothelium, Vascular - pathology
EphA2 protein
Flow cytometry
Gene expression
Gene Expression Regulation
Humans
Injuries
Lung diseases
Lung Injury - chemically induced
Lung Injury - genetics
Lung Injury - metabolism
Lung Injury - pathology
Lungs
Male
Mice
Mice, Inbred C57BL
MicroRNAs
MicroRNAs - genetics
Microvasculature
miRNA
Pathophysiology
Permeability
Proteins
Receptor, EphA2 - genetics
Receptor, EphA2 - metabolism
Ribonucleic acid
RNA
Target recognition
Therapeutic applications
Trachea
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Summary:MicroRNAs (miRNAs) are noncoding RNAs that regulate gene expression in many diseases, although the contribution of miRNAs to the pathophysiology of lung injury remains obscure. We hypothesized that dysregulation of miRNA expression drives the changes in key genes implicated in the development of lung injury. To test our hypothesis, we utilized a model of lung injury induced early after administration of intratracheal bleomycin (0.1 U). Wild-type mice were treated with bleomycin or PBS, and lungs were collected at 4 or 7 days. A profile of lung miRNA was determined by miRNA array and confirmed by quantitative PCR and flow cytometry. Lung miR-26a was significantly decreased 7 days after bleomycin injury, and, on the basis of enrichment of predicted gene targets, it was identified as a putative regulator of cell adhesion, including the gene targets EphA2, KDR, and ROCK1, important in altered barrier function. Lung EphA2 mRNA, and protein increased in the bleomycin-injured lung. We further explored the miR-26a/EphA2 axis in vitro using human lung microvascular endothelial cells (HMVEC-L). Cells were transfected with miR-26a mimic and inhibitor, and expression of gene targets and permeability was measured. miR-26a regulated expression of EphA2 but not KDR or ROCK1. Additionally, miR-26a inhibition increased HMVEC-L permeability, and the disrupted barrier integrity due to miR-26a was blocked by EphA2 knockdown, shown by VE-cadherin staining. Our data suggest that miR-26a is an important epigenetic regulator of EphA2 expression in the pulmonary endothelium. As such, miR-26a may represent a novel therapeutic target in lung injury by mitigating EphA2-mediated changes in permeability.
ISSN:1040-0605
1522-1504
DOI:10.1152/ajplung.00073.2017