Question:

This study was to detect which microRNAs (miRs) are regulated by chronic hypoxia (CH) in the mouse lung and to determine their functional significance in CH induced pulmonary hypertension (PH).

Methodology:

We detected miRs altered in mouse lung after 3 weeks CH (10% O₂) treatment by Microarray screening, verified miR target genes by reporter gene assay and Western blot. Furthermore, we analyzed in vitro and in vivo significance on cardiopulmonary function.

Results:

We discovered miR-223 was the most significantly decreased in the hypoxic mouse lung, which was also observed in the right ventricle (RV). IGF1R is a known target of miR-223 and demonstrated by 3’UTR reporter gene assay. IGF1R protein levels were increased in hypoxic mice lungs and RVs via a mechanism involving HIF1α/2α reduced C/EBPα expression and activity. Moreover, decreased IGF1R expression was detected in miR-223 overexpressing mouse pulmonary artery smooth muscle cell with attenuated IGF1-induced Akt phosphorylation, cell migration and proliferation. Decreasing endogenous miR-223 by antagomir, further increased hypoxia induced pulmonary artery pressure, vessel muscularization, RV hypertrophy and dysfunction. A similar phenomenon was also observed in miR-223^-/y mice. In lungs from primary PH patients we detected decreased miR-223 and increased IGF1R expression. Application of IGF1R antagonist was able to attenuate hypoxia induced pulmonary remodeling and improve RV function.

Conclusion:

These data indicate that hypoxia reduced expression of miR-223 in lung and RV contributes to development of hypoxic PH and cor pulmonale through increasing IGF1R expression and suggested a new direction for PH therapy through inhibiting IGF1R.