Susceptibility to high-altitude pulmonary edema is associated with circulating miRNA levels under hypobaric hypoxia conditions

Hypobaric hypoxia poses stress to sojourners traveling to high-altitude (HA). A cascade of physiological changes occurs to cope with or adapt to hypobaric hypoxia. However, an insufficient physiological response to the hypoxic condition due to imbalanced vascular homeostasis pathways results in high-altitude pulmonary edema (HAPE). The present study aims to identify the implication of miRNAs associating with HAPE and adaptation. We analyzed the expression of 1113 miRNAs in HAPE patients (HAPE-p), HAPE-free controls (HAPE-f), and highland natives (HLs). Based on miRNA profiling and in silico analyses, miR-124-3p emerged relevantly. We observed a significant over-expression of miR-124-3p in HAPE-p. In silico analyses revealed a direct interaction of miR-124-3p with vascular homeostasis and hypoxia associated genes, NOS3 (Endothelial Nitric Oxide Synthase), Apelin, and ETS1 (V-Ets Avian Erythroblastosis Virus E2 Oncogene Homolog 1). Moreover, the transcript and bio-level expression of these genes were significantly decreased in HAPE-p when compared with HAPE-f or HLs. Our in vitro analysis in HUVEC demonstrated a significant knockdown of these genes both at transcript and protein levels following miR-124-3p over-expression. Conclusively, our results showed that miR-124-3p might play a plausible role in HAPE pathophysiology by inhibiting the expression of NOS3, Apelin, and ETS1.

Keywords: HA adaptation; High-altitude pulmonary edema; Hypoxia; Vascular dysfunction; micro RNA.