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MiR-15a/16 Regulates Apoptosis of Lung Epithelial Cells after Oxidative Stress.


ABSTRACT: Lung epithelial cell apoptosis is an important feature of hyperoxia-induced lung injury. Death receptor-associated extrinsic pathway and mitochondria-associated intrinsic pathway both mediate the development of lung epithelial cell apoptosis. Despite decades of research, molecular mechanisms of hyperoxia-induced epithelial cell apoptosis remain incompletely understood. Here we report a novel regulatory paradigm in response to hyperoxia-associated oxidative stress. Hyperoxia markedly up-regulated miR-15a/16 levels in lung epithelial cells, broncho-alveolar lavage fluid (BALF) and lung tissue. This effect was mediated by hyperoxia-induced reactive oxygen species (ROS). Functionally, miR-15a/16 inhibitors induced caspase 3-mediated lung epithelial cell apoptosis, in the presence of hyperoxia. MiR-15a/16 inhibitors robustly enhanced FADD level and down-regulated Bcl-2 expression. Consistently, cleaved caspase 8 and 9 were highly induced in the miR-15a/16 deficient cells, after hyperoxia. Using airway epithelial cell specific, miR-15a/16-/- mice, we found that Bcl-2 significantly reduced in lung epithelial cells in vivo after hyperoxia. In contrast, caspase 3, 8 and Bcl-2 associated death promoter (BAD) were highly elevated in the miR-15a/16-/- epithelial cells in vivo. Interestingly, in lung epithelial malignant cells, rather than benign cells, deletion of miR-15a/16 prevented apoptosis. Furthermore, deletion of miR-15a/16 in macrophages also prohibited apoptosis, opposite to what we have found in normal lung epithelial cells. Taken together, our data suggested that miR-15a/16 may exert differential roles in different cell types. MiR-15a/16 deficiency result in lung epithelial cell apoptosis in response to hyperoxia, via modulating both intrinsic and extrinsic apoptosis pathways.

SUBMITTER: Cao Y 

PROVIDER: S-EPMC5023515 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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MiR-15a/16 Regulates Apoptosis of Lung Epithelial Cells after Oxidative Stress.

Cao Yong Y   Zhang Duo D   Moon Hyung-Geun HG   Lee Heedoo H   Haspel Jeffrey A JA   Hu Kebin K   Xie Lixin L   Jin Yang Y  

Molecular medicine (Cambridge, Mass.) 20160427


Lung epithelial cell apoptosis is an important feature of hyperoxia-induced lung injury. Death receptor-associated extrinsic pathway and mitochondria-associated intrinsic pathway both mediate the development of lung epithelial cell apoptosis. Despite decades of research, molecular mechanisms of hyperoxia-induced epithelial cell apoptosis remain incompletely understood. Here we report a novel regulatory paradigm in response to hyperoxia-associated oxidative stress. Hyperoxia markedly up-regulated  ...[more]

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