Roles of the hypoximir microRNA‐424/322 in acute hypoxia and hypoxia‐induced pulmonary vascular leakage

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‐1a, 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. FASEB J. 33, 12565–12575 (2019). www.fasebj.org