Inhibition of microRNA-17 improves lung and heart function in experimental pulmonary hypertension

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 hypertension (PH). We evaluated whether inhibition of these miRs may provide a novel therapeutic option. We first tested the effects of miR inhibitors (antagomirs), which were specifically designed to block miR-17 (A-17), -21 (A-21) and -92a (A-92a) in chronic hypoxia-induced PH in mice. A-17 and A-21 reduced right ventricular systolic pressure (RVSP) and all antagomirs decreased pulmonary arterial muscularization. However, only A-17 reduced hypoxia-induced right ventricular hypertrophy and improved pulmonary artery acceleration time (PAAT). Therefore, we additionally tested the effects of A-17 in monocrotaline-induced PH in rats. A-17 treatment significantly decreased RVSP and total pulmonary vascular resistance index, increased PAAT, normalized cardiac output and decreased pulmonary vascular remodelling. Among the tested miR-17 targets, the cyclin-dependent kinase inhibitor 1A (p21) was upregulated 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. Our data demonstrate that A-17 improves heart and lung function in experimental PH by interfering with lung vascular and right ventricular remodeling. Thus, inhibition of miR-17 may represent a novel therapeutic concept to ameliorate disease state in PH.