Question: 

The factors contributing to the development of chronic hypoxia-induced pulmonary hypertension (PH) and the subsequent right heart failure are not well understood. As microRNAs (miR) are important regulators of differentiation, proliferation and cell signaling pathways we analyzed the impact of miRs on the PH development and the associated right ventricular dysfunction.

Results: 

The expression of miR-223 was the most significantly decreased miR (micro arrays) in murine lungs after hypoxia treatment (3 weeks; 10% O_2.). The expression of miR-223 was also decreased in the right ventricle. The miR-223 target gene, IGF1R was verified by 3'UTR reporter assays and an increased expression of IGFR1 was demonstrated by Western blotting in lung and right ventricular tissue from hypoxia treated mice. AntagomiR treatment and knock out of miR-223 resulted in a more severe PH and right ventricular dysfunction compared to control animals. Pharmacological inhibition of the IGFR using GSK1904529A not only attenuated the pulmonary remodeling and improved cardiac function after hypoxia but also exerted beneficial effect on cardiac function in a model of pulmonary artery banding. In human lung samples from primary pulmonary hypertensive patients, miR-223 expression was decreased a phenomenon that was linked with a corresponding increase of IGFR1 expression compared to samples from healthy subjects.

Conclusion: 

These data demonstrate that the hypoxia-induced decrease in miR-223 expression in the lung and in the right ventricle contributes to the development of hypoxia-induced PH and right ventricular failure.