Inhibition of MicroRNA-17 Improves Lung and Heart Function in Experimental Pulmonary Hypertension

Max-Planck-Institute for Heart and Lung Research, Department of Lung Development and Remodeling, Bad Nauheim, Germany.
American Journal of Respiratory and Critical Care Medicine (Impact Factor: 13). 12/2011; 185(4):409-19. DOI: 10.1164/rccm.201106-1093OC
Source: PubMed


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

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Available from: Rajkumar Savai, Jun 28, 2015
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    • "This pathway is thought to be involved in the maintenance of pulmonary vasculature homeostasis and its dysfunction is associated with PAH (24,32). Induction of miR-21 expression was shown in the lungs of mice exposed to hypoxia (21,33), as well as in hypoxic PASMCs (32,33) and PAECs (34). miR-21 is also known to elicit anti-proliferative effects in both PAECs and PASMC (24,32,33). "
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    • "Subsequent studies showed that specific inhibition of these microRNAs by antagomiRs were found to restore functional levels of BMPR2 and to inhibit or even reverse the vascular remodeling and subsequent hemodynamic alterations [44,45]. "
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    • "MiRNAs are a class of small, noncoding RNAs that have critical post-transcriptional regulatory roles targeting mRNA with their main function being down-regulation of gene expression (Kim, 2005). MiRNAs are emerging as key, powerful transacting factors that regulate gene expression and fundamental cellular processes (Kim and Kim, 2012), and which may play an important role in the pathogenesis of PAH, including miR-17, miR-20a, and miR-21 (Brock et al., 2012; Parikh et al., 2012; Pullamsetti et al., 2012). In addition, a recent study identified two key endothelial miRNAs, miR-424 and miR-503, which are regulated by apelin-APJ signaling and which target two molecules of the FGF signaling pathway (FGF2 and fibroblast growth factor receptor 1, FGFR1), associated with the cellular hyperproliferation and vascular remodeling found in PAH. "
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