Question: 

Chronic hypoxia plays a key role in pulmonary hypertension,angiogenesis and remodeling by inducing marked changes in gene expersion, However, the regulatory effect of chronic hypoxia on microRNA(miR) expression in the lung has not yet been investigated. The purpose of this study was to determine which miRs are regualted by chronic hypoxia in mouse lung and to determine their functional significance.

Method: 

We identified miRs altered in mouse lung after 3 weeks chronic hypxoia (10% O₂) treatment by Microarray screening, verified miR target gene by reporter gene assays and western blotting, and analysed in vitro and in vivo functional significance for mouse pumonary vascular soomth muscle cells(mPSMC).

Results: 

Among the 4 up- and 4 down-regulated miRs, the most significant decrease observed was in the miR-223, verified by RT-qPCR. The insulin like growth factor 1 receptor (IGF1R) is a known target pf miR-223 and its protein level was increased by 30% in hypoxic mouse lung.Moreover, the IGF1R was decresed following introduction of pre-miR-223 as well as accompanied attenuation of IGF1-induced signaling i.e. Akt activiation, proliferation and migration in PSMC. Elevation of pulmonary artery pressure and vessel vascularization were found in antagomir treated or miR-223 KO mice. The attenuated miR-223 and increased IGF1R level were discovered in primary pulmonary hypertension patient samples.

Conclusion: 

The expression of miRs is modulated by choronic hypoxia, by down-regulation miR-223 contributes to the IGF1 regualted PSMC migration and thereby the hypoxia-reduced miR-223 might be involved in pulmonary remodeling.