Involvement of miRNA-34a regulated Krüppel-like factor 4 expression in hyperoxia-induced senescence in lung epithelial cells.
Autor: | Maeda H; Department of Molecular Biology, Cellular Biology, and Biochemistry, Division of Biology and Medicine, Brown University, Providence, RI, USA.; Department of Pediatrics, Fukushima Medical University School of Medicine, Fukushima, Japan., Yao H; Department of Molecular Biology, Cellular Biology, and Biochemistry, Division of Biology and Medicine, Brown University, Providence, RI, USA., Go H; Department of Pediatrics, Fukushima Medical University School of Medicine, Fukushima, Japan., Huntington KE; Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI, USA., De Paepe ME; Department of Pathology, Women and Infants Hospital, Providence, RI, USA., Dennery PA; Department of Molecular Biology, Cellular Biology, and Biochemistry, Division of Biology and Medicine, Brown University, Providence, RI, USA. phyllis_dennery@brown.edu.; Department of Pediatrics, Warren Alpert School of Medicine of Brown University, Providence, RI, USA. phyllis_dennery@brown.edu. |
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Jazyk: | angličtina |
Zdroj: | Respiratory research [Respir Res] 2022 Dec 10; Vol. 23 (1), pp. 340. Date of Electronic Publication: 2022 Dec 10. |
DOI: | 10.1186/s12931-022-02263-8 |
Abstrakt: | Background: Premature infants, subjected to supplemental oxygen and mechanical ventilation, may develop bronchopulmonary dysplasia, a chronic lung disease characterized by alveolar dysplasia and impaired vascularization. We and others have shown that hyperoxia causes senescence in cultured lung epithelial cells and fibroblasts. Although miR-34a modulates senescence, it is unclear whether it contributes to hyperoxia-induced senescence. We hypothesized that hyperoxia increases miR-34a levels, leading to cellular senescence. Methods: We exposed mouse lung epithelial (MLE-12) cells and primary human small airway epithelial cells to hyperoxia (95% O Results: Hyperoxia caused senescence as indicated by loss of nuclear lamin B1, increased p21 gene expression, and senescence-associated secretory phenotype factors. Expression of miR-34a-5p was increased in epithelial cells and newborn mice exposed to hyperoxia, and in premature infants requiring mechanical ventilation. Transfection with a miR-34a-5p inhibitor reduced hyperoxia-induced senescence in MLE-12 cells. Additionally, hyperoxia increased protein levels of the oncogene and tumor-suppressor Krüppel-like factor 4 (KLF4), which were inhibited by a miR-34a-5p inhibitor. Furthermore, KLF4 knockdown by siRNA transfection reduced hyperoxia-induced senescence. Conclusion: Hyperoxia increases miR-34a-5p, leading to senescence in lung epithelial cells. This is dictated in part by upregulation of KLF4 signaling. Therefore, inhibiting hyperoxia-induced senescence via miR-34a-5p or KLF4 suppression may provide a novel therapeutic strategy to mitigate the detrimental consequences of hyperoxia in the neonatal lung. (© 2022. The Author(s).) |
Databáze: | MEDLINE |
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