title: miR-185 mediates lung epithelial cell death after oxidative stress.
abstract: Lung epithelial cell death is a prominent feature involved in the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Hyperoxia-induced ALI is an established animal model mimicking human ARDS. Small noncoding RNAs such as microRNAs (miRNAs) have potent physiological and pathological functions involving multiple disease processes. Emerging interests focus on the potential of miRNAs to serve as novel therapeutic targets and diagnostic biomarkers. We found that hyperoxia highly induces miR-185 and its precursor in human lung epithelial cells in a time-dependent manner, and this observation is confirmed using mouse primary lung epithelial cells. The hyperoxia-induced miR-185 is mediated by reactive oxygen species. Furthermore, histone deacetylase 4 (HDAC4) locates in the promoter region of miR-185. We found that hyperoxia suppresses HDAC4 specifically in a time-dependent manner and subsequently affects histone deacetylation, resulting in an elevated miR-185 transcription. Using MC1586, an inhibitor of class IIa HDACs, we showed that inhibition of class IIa HDACs upregulates the expression of miR-185, mimicking the effects of hyperoxia. Functionally, miR-185 promotes hyperoxia-induced lung epithelial cell death through inducing DNA damage. We confirmed functional roles of miR-185 using both the loss- and gain-of-function approaches. Moreover, multiple 14-3-3δ pathway proteins are highly attenuated by miR-185 in the presence of hyperoxia. Taken together, hyperoxia-induced miR-185 in lung epithelial cells contributes to oxidative stress-associated epithelial cell death through enhanced DNA damage and modulation of 14-3-3δ pathways.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Boston University, Boston, Massachusetts;
authors.forename: Duo
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Boston University, Boston, Massachusetts;
authors.forename: Heedoo
authors.initials: H
authors.lastname: Lee
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Boston University, Boston, Massachusetts; Department of Respiratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China;
authors.forename: Yong
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Dela Cruz
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Boston University, Boston, Massachusetts; yjin1@bu.edu.
authors.forename: Yang
authors.initials: Y
authors.lastname: Jin
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism; D000107:Acetylation; D056809:Alveolar Epithelial Cells / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D019926:Cyclin B / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000502:physiology*; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D048948:14-3-3 Proteins; C503694:CCNB3 protein, human; D019926:Cyclin B; C552431:MIRN185 microRNA, human; D035683:MicroRNAs; D012097:Repressor Proteins; C400300:HDAC4 protein, human; D006655:Histone Deacetylases
keywords: cell death; epithelial cell; hyperoxia; miR-185; oxidative stress