PT  - JOURNAL ARTICLE
AU  - S. Pullamsetti
AU  - C. Doebele
AU  - A. Fischer
AU  - R. Savai
AU  - B. Kojonazarov
AU  - B. Dahal
AU  - H. Ghofrani
AU  - N. Weissmann
AU  - F. Grimminger
AU  - A. Bonauer
AU  - W. Seeger
AU  - A. Zeiher
AU  - S. Dimmeler
AU  - R. Schermuly
TI  - Role of microRNA 17/92 cluster and microRNA 21 in the pathogenesis of pulmonary hypertension - Novel therapeutic targets
DP  - 2013 Sep 01
TA  - European Respiratory Journal
PG  - P5160
VI  - 42
IP  - Suppl 57
4099  - http://erj.ersjournals.com/content/42/Suppl_57/P5160.short
4100  - http://erj.ersjournals.com/content/42/Suppl_57/P5160.full
SO  - Eur Respir J2013 Sep 01; 42
AB  - MicroRNAs (miRs) control various cellular processes in tissue homeostasis and disease by regulating gene expression on the post-transcriptional level. Recently, it was demonstrated that expression of miR-21 and miR-17–92 cluster was significantly altered in pulmonary hypertension (PH).To evaluate the therapeutic efficacy and anti-remodeling potential of miR inhibitors in the pathogenesis of PH, we used 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 (HOX-PH) in mice and A-17 in monocrotaline-induced PH (MCT-PH) in rats. Moreover, biological function of miR-17 was analyzed in pulmonary artery smooth muscle cells (PASMCs).In HOX-PH mouse model, A-17 and A- 21 reduced right ventricular systolic pressure (RVSP). However, only A-17 reduced hypoxia-induced right ventricular hypertrophy and improved pulmonary artery acceleration time (PAAcT). In the MCT-PH rat model, A-17 treatment significantly decreased RVSP, increased PAAcT, normalized cardiac output, and decreased pulmonary vascular remodeling. Among the tested miR-17 targets, p21, BMPR2 and ID1 were upregulated in lungs undergoing A-17 treatment. Likewise, in human PASMCs, A-17 increased p21. Overexpression of miR-17 significantly reduced p21 expression and increased proliferation of PASMCs.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 upregulation of p21. Thus, inhibition of miR-17 may represent a novel therapeutic concept for treatment of PH.