title: microRNA-1246 mediates lipopolysaccharide-induced pulmonary endothelial cell apoptosis and acute lung injury by targeting angiotensin-converting enzyme 2.
abstract: In this study, we aimed to identify potential microRNA (miRNA) regulators of angiotensin-converting enzyme 2 (ACE2) and to explore their roles in lipopolysaccharide (LPS)-induced acute lung injury (ALI). The expression of predicted miRNA regulators of ACE2 was examined in LPS-exposed pulmonary microvascular endothelial cells (PMVECs). Gain- and loss-of-function studies were performed to determine the functions of candidate miRNAs in LPS-induced PMVEC apoptosis and inflammatory response. The roles of the miRNAs in LPS-induced lung inflammation and permeability were investigated in a mouse model. Notably, LPS (1 μg/mL) significantly induced the expression of miR-1246 in PMVECs. ACE2 was validated as a target gene of miR-1246. Silencing of miR-1246 prevented LPS-induced inhibition of ACE2, which was accompanied by reduced apoptosis and production of IL-1β and TNF-α. In contrast, ectopic expression of miR-1246 triggered apoptosis in PMVECs and promoted IL-1β and TNF-α release. MiR-1246-mediated apoptosis of PMVECs was impaired by overexpression of ACE2. Depletion of miR-1246 attenuated lung inflammation, neutrophil infiltration, and vascular permeability and restored pulmonary expression of ACE2 in LPS-exposed mice. Taken together, miR-1246 meditates LPS-induced pulmonary endothelial cell apoptosisin vitroand ALI in mouse models, which are, at least partially, ascribed to repression of ACE2.
authors.affiliation: Department of Pharmacy, First People's Hospital Affiliated to Shanghai Jiaotong University Shanghai, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Department of Respiratory Medicine, Shanghai Jiangong Hospital Shanghai, China.
authors.forename: Fengying
authors.initials: F
authors.lastname: Gao
authors.affiliation: Department of Nephrology, First People's Hospital Affiliated to Shanghai Jiaotong University Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Hao
authors.affiliation: Department of Respiratory Medicine, Shanghai General Hospital, Shanghai Jiaotong University Shanghai, China.
authors.forename: Zhenwei
authors.initials: Z
authors.lastname: Liu
keywords: ACE2; apoptosis; inflammation; lung injury; microRNA; target genes