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Am J Respir Crit Care Med. 2012 Feb 15;185(4):409-19. doi: 10.1164/rccm.201106-1093OC. Epub 2011 Dec 8.

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

Author information

1
Max-Planck-Institute for Heart and Lung Research, Department of Lung Development and Remodeling, Bad Nauheim, Germany.

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.

PMID:
22161164
DOI:
10.1164/rccm.201106-1093OC
[Indexed for MEDLINE]
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