Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
Department of Physiology and Biophysics, Graduate Institute of Physiology, National Defense Medical Center, Taipei, Taiwan.
FASEB J. 2019 Nov;33(11):12565-12575. doi: 10.1096/fj.201900564RR. Epub 2019 Aug 28.
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 . 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.
急性高原病（AMS）发生在高达 25%的未适应的人上升到 3000 米，可导致高原肺水肿（HAPE）。 microRNAs（miRs）可以在转录后水平调节基因表达。缺氧通过缺氧诱导因子-1α（HIF-1α）依赖性机制选择性地破坏内皮紧密连接复合物。虽然在缺氧的早期阶段，HIF-1α的表达增加与 AMS 发展的适应和保护有关，但 HIF-1α的下游效应物 VEGF 可诱导过度的内皮屏障功能障碍，增加血管通透性，并最终导致 HAPE 和高海拔脑水肿。我们假设，miRs 对下游效应物的精细调节对于维持内皮屏障完整性和防止血管渗漏至关重要。我们发现，在被置于 3100 米高度的健康志愿者中，几种 miRs 上调。通过回顾文献并使用在线生物信息学预测软件，我们特别选择 miR-424 进行进一步研究，因为它可以调节 HIF-1α和 VEGF。缺氧诱导的 miR-424 过表达依赖于 HIF-1α，miR-424 稳定 HIF-1α，降低 VEGF 表达，并促进血管内皮钙黏蛋白磷酸化。此外，缺氧导致内皮屏障功能障碍，通透性增加；miR-424 因此减轻了缺氧诱导的内皮细胞衰老和凋亡。miR-322 敲除小鼠易发生缺氧诱导的肺血管渗漏。miR-322 模拟物改善了缺氧诱导的肺血管渗漏。我们得出的结论是，在暴露于低压缺氧的健康成年志愿者中，几种 miRs 上调。miR-424/322 可以调节 HIF-1α-VEGF 轴，并在缺氧条件下防止缺氧诱导的肺血管渗漏。-Tsai，S.-H.，Huang，P.-H.，Tsai，H.-Y.，Hsu，Y.-J.，Chen，Y.-W.，Wang，J.-C.，Chen，Y.-H.，Lin，S.-J. 低氧诱导 microRNA-424/322 在急性缺氧和缺氧诱导的肺血管渗漏中的作用。
