Document Detail


A role for miR-145 in pulmonary arterial hypertension: evidence from mouse models and patient samples.
MedLine Citation:
PMID:  22715469     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
RATIONALE: Despite improved understanding of the underlying genetics, pulmonary arterial hypertension (PAH) remains a severe disease. Extensive remodeling of small pulmonary arteries, including proliferation of pulmonary artery smooth muscle cells (PASMCs), characterizes PAH. MicroRNAs (miRNAs) are noncoding RNAs that have been shown to play a role in vascular remodeling. Objective: We assessed the role of miR-145 in PAH.
METHODS AND RESULTS: We localized miR-145 in mouse lung to smooth muscle. Using quantitative PCR, we demonstrated increased expression of miR-145 in wild-type mice exposed to hypoxia. PAH was evaluated in miR-145 knockout and mice treated with anti-miRs via measurement of systolic right ventricular pressure, right ventricular hypertrophy, and percentage of remodeled pulmonary arteries. miR-145 deficiency and anti-miR-mediated reduction resulted in significant protection from the development of PAH. In contrast, miR-143 anti-miR had no effect. Furthermore, we observed upregulation of miR-145 in lung tissue of patients with idiopathic and heritable PAH compared with unaffected control subjects and demonstrated expression of miR-145 in SMC of remodeled vessels from such patients. Finally, we show elevated levels of miR-145 expression in primary PASMCs cultured from patients with BMPR2 mutations and also in the lungs of BMPR2-deficient mice.
CONCLUSIONS: miR-145 is dysregulated in mouse models of PAH. Downregulation of miR-145 protects against the development of PAH. In patient samples of heritable PAH and idiopathic PAH, miR-145 is expressed in remodeled vessels and mutations in BMPR2 lead to upregulation of miR-145 in mice and PAH patients. Manipulation of miR-145 may represent a novel strategy in PAH treatment.
Authors:
Paola Caruso; Yvonne Dempsie; Hannah C Stevens; Robert A McDonald; Lu Long; Ruifang Lu; Kevin White; Kirsty M Mair; John D McClure; Mark Southwood; Paul Upton; Mei Xin; Eva van Rooij; Eric N Olson; Nicholas W Morrell; Margaret R MacLean; Andrew H Baker
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-06-19
Journal Detail:
Title:  Circulation research     Volume:  111     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-07-23     Completed Date:  2012-10-02     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  290-300     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Disease Models, Animal*
Down-Regulation / genetics
Female
Gene Knock-In Techniques
Humans
Hypertension, Pulmonary / genetics*,  pathology*,  prevention & control
Lung / pathology,  physiology
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Knockout
MicroRNAs / antagonists & inhibitors,  genetics,  physiology*
Grant Support
ID/Acronym/Agency:
BB/FOF/280//Biotechnology and Biological Sciences Research Council; RG/08/002/24718//British Heart Foundation; SP/10/7/28383//British Heart Foundation; //Medical Research Council
Chemical
Reg. No./Substance:
0/MIRN145 microRNA, mouse; 0/MicroRNAs

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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