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). http://www.fasebj.org

The multiple organs insult and compensation mechanism in mice exposed to hypobaric hypoxia

“…And persons who are not acclimatized and ascend rapidly to elevations above 2500 m are at risk for any of several debilitating and potentially lethal illnesses including AMS, HACE, and HAPE that occur within the first days after arrival at high altitudes, leading to considerable morbidity and mortality, if not diagnosed or treated in a timely way (West 2014 ; Luks et al 2014 ; Bärtsch and Swenson 2013 ). Studies have reported that AMS occurs in approximately 10 to 25% of unacclimatized persons who ascend to 2500 m, and 50 to 85% at 4500 to 5500 m, and may be incapacitating (Tsai et al 2019 ; Maggiorini et al 1990 ; Sánchez-Mascuñano et al 2017 ). The prevalence of HACE is estimated to be 0.5 to 1.0% among persons at 4000 to 5000 m (Zhou et al 2017 ).…”

MIR17HG polymorphisms contribute to High altitude pulmonary edema susceptibility in Chinese Han people

“…Studies have confirmed that p53 and HIF-1α can inhibit the expression of miR-17-92 gene cluster [19]. And study finds increased expression of HIF-1a is associated with hypoxia adaptation [20]. The MIR17HG gene locus encodes the miR-17-92 gene cluster (MIR17HG), the family members of this gene cluster are widely involved in the functional regulation of vascular ECs [21].…”

Investigation of the gene co-expression network and hub genes associated with acute mountain sickness

“…There have been not any significant critical contrasts of the association among these modules, demonstrating the higher scale independence. Those symbols M stands to the module, and the number in the brackets speaks to those amount of genes in the module hypoxia leads to hypoxia-inducible factor-1α (HIF-1α) expression and endothelial barrier dysfunction in healthy adult volunteers ascend to 3100 m height [27]. Yang YD et al suggested that cell apoptosis is related to mitochondria-associated membranes in hypoxia-induced endothelial injury [28].…”