MicroRNA-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. 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.

MicroRNA Expression in Extracellular Vesicles from Nasal Lavage Fluid in Chronic Rhinosinusitis

“…Assessment of the genes targeted by miR-23a-3p, miR-15a-5p, miR-223-3p, and miR-1285-3p involved in the mucin-type O-glycan biosynthetic signaling pathway predicted representatively the MET proto-oncogene (MET), epidermal growth factor receptor (EGFR), beta-actin (ACTB), transforming growth factor beta receptor (TGF-βR), and poly(ADP-ribose) polymerase 1 (PARP1). The previous studies shown in Table 3 showed each miRNA’s role in disease progression, fibrosis, and inflammation, which was consistent with our results with regard to inflammatory diseases, but opposite results were also confirmed in some references denoted with asterisks [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ].…”

Caveolin-1 selectively regulates microRNA sorting into microvesicles after noxious stimuli

“…All animal experiments were performed in accordance with the approved guidelines. For normoxia and hyperoxia conditions, mice were exposed to room air and hyperoxia (100% oxygen), respectively, as previously described ( Cao et al, 2016 ).…”

Investigation of MicroRNA Expression in Anterior Lens Capsules of Senile Cataract Patients and MicroRNA Differences According to the Cataract Type

“… 28 Overexpression of miR-23a∼27a∼24-2 cluster increased ROS production and induced caspase-dependent and -independent apoptosis in human embryonic kidney cells. 29 Cao et al 30 reported that miR-15a/16 deficiency resulted in lung epithelial cell apoptosis in response to hyperoxia, by modulating both intrinsic and extrinsic apoptosis.…”