Document Type
Article
Publication Date
4-11-2025
Publication Title
Cardiovascular Toxicology
Abstract
Particulate matter containing environmentally persistent free radicals (EPFRs) is formed when organic pollutants are incompletely burned and adsorb to the surface of particles containing redox-active metals. Our prior studies showed that in mice, EPFR inhalation impaired vascular relaxation in a dose- and endothelium-dependent manner. We also observed that activation of the aryl hydrocarbon receptor (AhR) in the alveolar type-II (AT-II) cells that form the air-blood interface stimulates the release of systemic factors that promote endothelial dysfunction in vessels peripheral to the lung. AhR is a recognized regulator of microRNA (miRNA) biogenesis, and miRNA control diverse signaling pathways. We thus hypothesized that systemic EPFR-induced vascular endothelial dysfunction is initiated via AhR activation in AT-II cells, resulting in a systemic release of miRNA. Using a combustion reactor, we generated EPFR of two free radical concentrations—EPFRlo (1016–17 radicals/g particles) and EPFR (1018–19 radicals/g)—and exposed mice by inhalation. EFPR inhalation resulted in changes in a distinct array of miRNA in the plasma, and these miRNAs are linked to multiple systemic effects, including cardiovascular diseases and dysregulation of cellular and molecular pathways associated with cardiovascular dysfunction. We identified 17 miRNA in plasma that were altered dependent upon both AhR activation in AT-II cells and ~ 280 ug/m3 EPFR exposure. Using Ingenuity Pathway Analysis, we found that 5 of these miRNAs have roles in modulating endothelin-1 and endothelial nitric oxide signaling, known regulators of endothelial function. Furthermore, EPFR exposure reduced the expression of lung adherens and gap junction proteins in control mice but not AT-II-AhR deficient mice, and reductions in barrier function may facilitate miRNA release from the lungs. In summary, our findings support that miRNA may be systemic mediators promoting endothelial dysfunction mediated via EPFR-induced AhR activation at the air-blood interface.
First Page
651
Last Page
665
PubMed ID
40214911
Volume
25
Issue
5
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Recommended Citation
Aryal, Ankit; Harmon, Ashlyn C.; Noël, Alexandra; Yu, Qingzhao; Varner, Kurt J.; and Dugas, Tammy R., "AhR Activation at the Air-Blood Barrier Alters Systemic microRNA Release After Inhalation of Particulate Matter Containing Environmentally Persistent Free Radicals" (2025). School of Public Health Faculty Publications. 486.
https://digitalscholar.lsuhsc.edu/soph_facpubs/486
10.1007/s12012-025-09989-z
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Biostatistics Commons, Comparative and Laboratory Animal Medicine Commons, Medical Pharmacology Commons