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Roles of the hypoximir microRNA-424/322 in acute hypoxia and hypoxia-induced pulmonary vascular leakage.
Tsai, Shih-Hung; Huang, Po-Hsun; Tsai, Hsiao-Ya; Hsu, Yu-Juei; Chen, Yen-Wen; Wang, Jen-Chun; Chen, Ying-Hsin; Lin, Shing-Jong.
Affiliation
  • Tsai SH; Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
  • Huang PH; Department of Physiology and Biophysics, Graduate Institute of Physiology, National Defense Medical Center, Taipei, Taiwan.
  • Tsai HY; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
  • Hsu YJ; Division of Cardiology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
  • Chen YW; Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan.
  • Wang JC; Department of Critical Care Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
  • Chen YH; Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
  • Lin SJ; Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
FASEB J ; 33(11): 12565-12575, 2019 11.
Article in En | MEDLINE | ID: mdl-31461385
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Brain Edema / Capillary Permeability / MicroRNAs / Altitude Sickness / Human Umbilical Vein Endothelial Cells / Lung Diseases / Hypoxia Type of study: Observational_studies / Prognostic_studies / Risk_factors_studies Limits: Animals / Female / Humans / Male Language: En Journal: FASEB J Journal subject: BIOLOGIA / FISIOLOGIA Year: 2019 Type: Article Affiliation country: Taiwan

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Brain Edema / Capillary Permeability / MicroRNAs / Altitude Sickness / Human Umbilical Vein Endothelial Cells / Lung Diseases / Hypoxia Type of study: Observational_studies / Prognostic_studies / Risk_factors_studies Limits: Animals / Female / Humans / Male Language: En Journal: FASEB J Journal subject: BIOLOGIA / FISIOLOGIA Year: 2019 Type: Article Affiliation country: Taiwan