Abstract
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.
- © 2011 ERS