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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    ABSTRACT: microRNAs (miRNAs) are a class of small, non-coding RNAs that play critical posttranscriptional regulatory roles typically through targeting of the 3'-untranslated region of messenger RNA (mRNA). Mature miRNAs are known to be involved in global cellular processes, such as differentiation, proliferation, apoptosis, and organogenesis, due to their capacity to target multiple mRNAs. Thus, imbalances in the expression and/or activity of miRNAs are involved in the pathogenesis of numerous diseases, including pulmonary arterial hypertension (PAH). PAH is a progressive disease characterized by vascular remodeling due to excessive proliferation of pulmonary artery endothelial cells (PAECs) and pulmonary artery smooth muscle cells (PASMCs). Recently, studies have evaluated the roles of miRNAs involved in the pathogenesis of PAH in these pulmonary vascular cells. This review provides an overview of recent discoveries on the role of miRNAs in the pathogenesis of PAH and discusses the potential for miRNAs as therapeutic targets and biomarkers of PAH.
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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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    ABSTRACT: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by the vascular remodeling of the pulmonary arterioles, including formation of plexiform and concentric lesions comprised of proliferative vascular cells. Clinically, PAH leads to increased pulmonary arterial pressure and subsequent right ventricular failure. Existing therapies have improved the outcome but mortality still remains exceedingly high. There is emerging evidence that the seven-transmembrane G-protein coupled receptor APJ and its cognate endogenous ligand apelin are important in the maintenance of pulmonary vascular homeostasis through the targeting of critical mediators, such as Krűppel-like factor 2 (KLF2), endothelial nitric oxide synthase (eNOS), and microRNAs (miRNAs). Disruption of this pathway plays a major part in the pathogenesis of PAH. Given its role in the maintenance of pulmonary vascular homeostasis, the apelin-APJ pathway is a potential target for PAH therapy. This review highlights the current state in the understanding of the apelin-APJ axis related to PAH and discusses the therapeutic potential of this signaling pathway as a novel paradigm of PAH therapy.
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