MicroRNA-15a/16 Regulates Apoptosis of Lung Epithelial Cells After Oxidative Stress

Autor: Yong Cao, Duo Zhang, Hyung-Geun Moon, Heedoo Lee, Jeffrey A Haspel, Kebin Hu, Lixin Xie, Yang Jin
Jazyk: angličtina
Rok vydání: 2016
Předmět:
Zdroj: Molecular Medicine, Vol 22, Iss 1, Pp 233-243 (2016)
Druh dokumentu: article
ISSN: 1076-1551
1528-3658
DOI: 10.2119/molmed.2015.00136
Popis: Abstract Lung epithelial cell apoptosis is an important feature of hyperoxia-induced lung injury. The 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 upregulated microRNA (miR)-15a/16 levels in lung epithelial cells, bronchoalveolar lavage fluid (BALF) and lung tissue. This effect was mediated by hyperoxia-induced reactive oxygen species. 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 downregulated 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 was significantly reduced in lung epithelial cells in vivo after hyperoxia. In contrast, caspase-3, caspase-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, which is the opposite of 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 results in lung epithelial cell apoptosis in response to hyperoxia, via modulating both intrinsic and extrinsic apoptosis pathways.
Databáze: Directory of Open Access Journals
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