Document Detail


Inhibition of microRNA-17 Improves Lung and Heart Function in Experimental Pulmonary Hypertension.
MedLine Citation:
PMID:  22161164     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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). Objective - We intend to evaluate the therapeutic efficacy and anti-remodeling potential of miR inhibitors in the pathogenesis of PH. Methods and Results - 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. 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 PAAcT, normalized cardiac output and decreased pulmonary vascular remodeling. 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. Conclusion - 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 upregulation of p21. Thus, inhibition of miR-17 may represent a novel therapeutic concept to ameliorate disease state in PH.
Authors:
Soni S Pullamsetti; Carmen Doebele; Ariane Fischer; Rajkumar Savai; Baktybek Kojonazarov; Bhola K Dahal; Hossein A Ghofrani; Norbert Weissmann; Friedrich Grimminger; Angelika Bonauer; Werner Seeger; Andreas M Zeiher; Stefanie Dimmeler; Ralph T Schermuly
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-12-8
Journal Detail:
Title:  American journal of respiratory and critical care medicine     Volume:  -     ISSN:  1535-4970     ISO Abbreviation:  -     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-12-13     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9421642     Medline TA:  Am J Respir Crit Care Med     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Department of Lung Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, bad nauheim, Germany.
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