Journal article

Publication year: 2012

Pages: 409-419

Journal: American Journal of Respiratory and Critical Care Medicine

Volume number: 185

Issue number: 4

ISSN: 1073-449X

eISSN: 1535-4970

DOI Link: https://doi.org/10.1164/rccm.201106-1093OC

Publisher: American Thoracic Society

Abstract: 

Rationale: MicroRNAs (miRs) control various cellular processes in tissue homeostasis and disease by regulating gene expression on the posttranscriptional level. Recently, it was demonstrated that the expression of miR-21 and members of the miR-17-92 cluster was significantly altered in experimental pulmonary hypertension (PH).

Objectives: To evaluate the therapeutic efficacy and antiremodeling potential of miR inhibitors in the pathogenesis of PH.

Methods: We first tested the effects of miR inhibitors (antagomirs), which were specifically designed to block miR-17 (A-17), miR-21 (A-21), and miR-92a (A-92a) in chronic hypoxia-induced PH in mice and A-17 in monocrotaline-induced PH in rats. Moreover, biological function of miR-17 was analyzed in cultured pulmonary artery smooth muscle cells.

Measurements and Main Results: In the PH mouse model, A-17 and A-21 reduced right ventricular systolic pressure, and all antagomirs decreased pulmonary arterial muscularization. However, only A-17 reduced hypoxia-induced right ventricular hypertrophy and improved pulmonary artery acceleration time. In the monocrotaline-induced PH rat model, A-17 treatment significantly decreased right ventricular systolic pressure and total pulmonary vascular resistance index, increased pulmonary artery acceleration time, normalized cardiac output, and decreased pulmonary vascular remodeling. Among the tested miR-17 targets, the cyclin-dependent kinase inhibitor 1A (p21) was up-regulated in lungs undergoing A-17 treatment. Likewise, in human pulmonary artery smooth muscle cells, A-17 increased p21. Overexpression of miR-17 significantly reduced p21 expression and increased proliferation of smooth muscle cells.

Conclusions: Our data demonstrate that A-17 improves heart and lung function in experimental PH by interfering with lung vascular and right ventricular remodeling. The beneficial effects may be related to the up-regulation of p21. Thus, inhibition of miR-17 may represent a novel therapeutic concept to ameliorate disease state in PH.

Harvard Citation style: Pullamsetti, S., Doebele, C., Fischer, A., Savai, R., Kojonazarov, B., Dahal, B., et al. (2012) Inhibition of MicroRNA-17 Improves Lung and Heart Function in Experimental Pulmonary Hypertension, American Journal of Respiratory and Critical Care Medicine, 185(4), pp. 409-419. https://doi.org/10.1164/rccm.201106-1093OC

APA Citation style: Pullamsetti, S., Doebele, C., Fischer, A., Savai, R., Kojonazarov, B., Dahal, B., Ghofrani, H., Weissmann, N., Grimminger, F., Bonauer, A., Seeger, W., Zeiher, A., Dimmeler, S., & Schermuly, R. (2012). Inhibition of MicroRNA-17 Improves Lung and Heart Function in Experimental Pulmonary Hypertension. American Journal of Respiratory and Critical Care Medicine. 185(4), 409-419. https://doi.org/10.1164/rccm.201106-1093OC