Document Detail


MiRNA-21/DDAH1 pathway regulates pulmonary vascular responses to hypoxia.
MedLine Citation:
PMID:  24895913     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
The nitric oxide synthase (NOS) inhibitor, asymmetric dimethylarginine (ADMA), contributes to the pathogenesis of pulmonary hypertension. Reduced levels of the enzymes metabolising ADMA, dimethylarginine dimethylaminohydrolases (DDAH1 and DDAH2) and increased levels of miRNA-21 are linked to disease pathology, but the mechanisms are not understood. Here we studied the potential role of miRNA-21 in the regulation of hypoxia-induced changes in ADMA metabolism in vitro and in vivo. Hypoxia inhibited DDAH1 and DDAH2 expression and increased ADMA levels in cultured human pulmonary endothelial cells. In contrast, in human pulmonary smooth muscle cells only DDAH2 was reduced while ADMA levels remained unchanged. Endothelium-specific downregulation of DDAH1 by microRNA-21 in hypoxia induced endothelial dysfunction and was prevented by overexpression of DDAH1 and miRNA-21 blockade. DDAH1 but not DDAH2 mRNA levels were reduced while miRNA-21 levels were elevated in lung tissues from patients with pulmonary arterial hypertension and pulmonary hypertensive mice exposed to 2 weeks hypoxia. Hypoxic mice treated with miRNA-21 inhibitors and DDAH1 transgenic mice showed elevated lung DDAH1, increased cGMP levels and attenuated pulmonary hypertension. Regulation of DDAH1 by miRNA-21 plays a role in development of hypoxia-induced pulmonary hypertension and may be of broader significance in pulmonary hypertension.
Authors:
Lucio Iannone; Lan Zhao; Olivier Dubois; Lucie Duluc; Christopher J Rhodes; John Wharton; Martin R Wilkins; James Leiper; Beata Wojciak-Stothard
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-6-4
Journal Detail:
Title:  The Biochemical journal     Volume:  -     ISSN:  1470-8728     ISO Abbreviation:  Biochem. J.     Publication Date:  2014 Jun 
Date Detail:
Created Date:  2014-6-4     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2984726R     Medline TA:  Biochem J     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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