Downregulation of lung miR-203a-3p expression by high-altitude hypoxia enhances VEGF/Notch signaling

Abstract

Hypoxia-related microRNAs (miRNAs) are involved in the pathogenesis of various diseases. Because potential variations in miRNA expression mediated by hypoxic lung injury at high altitude remain incompletely characterized, we used a rat model to investigate the biochemical and miRNA changes induced by high-altitude hypoxia. After 24, 48, or 72 h of hypoxic exposure, expression of VEGF/Notch pathway-related proteins were increased in rat lung tissues. Microarray screening of hypoxic lung samples revealed 57 differentially expressed miRNAs, 19 of which were related to the VEGF/Notch signaling pathway. We verified that the top downregulated miRNA (miR-203a-3p) suppresses VEGF-A translation through direct binding and also indirectly reduces Notch1, VEGFR2, and Hes1 levels, which restricts the angiogenic capacity of pulmonary microvascular endothelial cells in vitro. These findings may aid in the development of new therapeutic strategies for the prevention and treatment of hypoxic lung injury at high altitude.

MicroRNA-361-5p Aggravates Acute Pancreatitis by Promoting Interleukin-17A Secretion via Impairment of Nuclear Factor IA-Dependent Hes1 Downregulation

“…Given these findings, we concluded that overexpression of NFIA might potentially diminish the expression of Hes1 and thereby reduce the secretion of IL-17A. More importantly, several miRNAs, including miR-203a-3p and miR-146a, are directly correlated with the increased Hes1 levels. , The present study clarified the promoting effect of miR-361-5p on Hes1 expression. This suggested that miR-361-5p could augment Hes1 expression by targeting NFIA, thus potentiating IL-17A secretion and the resultant acute pancreatitis progression.…”

Comprehensive Analysis of Long Non-coding RNA and mRNA Transcriptomes Related to Hypoxia Adaptation in Tibetan Sheep

“…Along with human migration and settlement, many domestic animals have reproduced for generations in these harsh living conditions and have thus adapted unique and distinctive characteristics at the morphological, physiological and genetic levels ( 1 – 3 ). Scientists have used large-scale omics data to reveal the adaptive genetic mechanisms of domestic animals on the Qinghai-Tibet Plateau and identified a number of plateau-adaptive candidate genes, including EPAS1 (endothelial PAS domain-containing protein 1), EGLN1 (Egl-9 homolog 1) and VEGF (vascular endothelial growth factor), in the HIF (hypoxia inducible factor) hypoxia-inducing pathway ( 4 – 7 ).…”

Relationship between chronic hypoxia and seizure susceptibility

“…Activated microglia, astrocytes, and their corresponding M1 and A1 glial subtypes can enhance seizure susceptibility in various ways F I G U R E 4 Chronic hypoxia and secondary neuroinflammation can activate astrocytes and decrease their normal physiological function, with changes in the expression of excitatory amino acid transporters, ion channels, connexin, and AQP4. These changes enhance seizure susceptibility by promoting intracellular chloride deposition, reducing glutamate reuptake, promoting glutamate release secondary to cell swelling, increasing extracellular glutamate concentrations, and reducing GABAergic neuronal inhibition 2.2.2 | Chronic hypoxia causes abnormal activation and proliferation of astrocytes Chronic hypoxia may promote the abnormal proliferation and activation of astrocytes by activating VEGF or Notch-1 pathways [35][36][37][38][39] (Figure 4). Neuroinflammation secondary to chronic hypoxia can also abnormally activate astrocytes and affect their normal physiological functions.…”

“…Chronic hypoxia may promote the abnormal proliferation and activation of astrocytes by activating VEGF or Notch‐1 pathways 35 , 36 , 37 , 38 , 39 (Figure 4 ). Neuroinflammation secondary to chronic hypoxia can also abnormally activate astrocytes and affect their normal physiological functions.…”