Roles of the hypoximir microRNA-424/322 in acute hypoxia and hypoxia-induced pulmonary vascular leakage.
FASEB J
; 33(11): 12565-12575, 2019 11.
Article
em En
| MEDLINE
| ID: mdl-31461385
ABSTRACT
Acute mountain sickness (AMS) occurs in up to 25% of unacclimatized persons who ascend to 3000 m and can result in high-altitude pulmonary edema (HAPE). MicroRNAs (miRs) can regulate gene expression at the post-transcriptional level. Hypoxia selectively disrupts endothelial tight junction complexes through a hypoxia-inducible factor-1α (HIF-1α)-dependent mechanism. Though increased HIF-1α expression is associated with adaptation and protection from AMS development in the early stage of hypoxia, a downstream effector of HIF-1α, VEGF, can induce overzealous endothelial barrier dysfunction, increase vascular permeability, and ultimately result in HAPE and high-altitude cerebral edema. We hypothesized that the fine-tuning of downstream effectors by miRs is paramount for the preservation of endothelial barrier integrity and the prevention of vascular leakage. We found that several miRs were up-regulated in healthy volunteers who were subjected to a 3100-m height. By reviewing the literature and using online bioinformatics prediction software, we specifically selected miR-424 for further investigation because it can modulate both HIF-1α and VEGF. Hypoxia-induced miR-424 overexpression is HIF-1α dependent, and miR-424 stabilized HIF-1α, decreased VEGF expression, and promoted vascular endothelial cadherin phosphorylation. In addition, hypoxia resulted in endothelial barrier dysfunction with increased permeability; miR-424 thus attenuated hypoxia-induced endothelial cell senescence and apoptosis. miR-322 knockout mice were susceptible to hypoxia-induced pulmonary vascular leakage. miR-322 mimics improved hypoxia-induced pulmonary vascular leakage in vivo. We conclude that several miRs were up-regulated in healthy adult volunteers subjected to hypobaric hypoxemia. miR-424/322 could modulate the HIF-1α-VEGF axis and prevent hypoxia-induced pulmonary vascular leakage under hypoxic conditions.-Tsai, S.-H., Huang, P.-H., Tsai, H.-Y., Hsu, Y.-J., Chen, Y.-W., Wang, J.-C., Chen, Y.-H., Lin, S.-J. Roles of the hypoximir microRNA-424/322 in acute hypoxia and hypoxia-induced pulmonary vascular leakage.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Edema Encefálico
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Permeabilidade Capilar
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MicroRNAs
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Doença da Altitude
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Células Endoteliais da Veia Umbilical Humana
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Pneumopatias
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Hipóxia
Tipo de estudo:
Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article