Document Detail


Therapeutic inhibition of the miR-34 family attenuates pathological cardiac remodeling and improves heart function.
MedLine Citation:
PMID:  23047694     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
MicroRNAs are dysregulated in a setting of heart disease and have emerged as promising therapeutic targets. MicroRNA-34 family members (miR-34a, -34b, and -34c) are up-regulated in the heart in response to stress. In this study, we assessed whether inhibition of the miR-34 family using an s.c.-delivered seed-targeting 8-mer locked nucleic acid (LNA)-modified antimiR (LNA-antimiR-34) can provide therapeutic benefit in mice with preexisting pathological cardiac remodeling and dysfunction due to myocardial infarction (MI) or pressure overload via transverse aortic constriction (TAC). An additional cohort of mice subjected to MI was given LNA-antimiR-34a (15-mer) to inhibit miR-34a alone as a comparison for LNA-antimiR-34. LNA-antimiR-34 (8-mer) efficiently silenced all three miR-34 family members in both cardiac stress models and attenuated cardiac remodeling and atrial enlargement. In contrast, inhibition of miR-34a alone with LNA-antimiR-34a (15-mer) provided no benefit in the MI model. In mice subjected to pressure overload, LNA-antimiR-34 improved systolic function and attenuated lung congestion, associated with reduced cardiac fibrosis, increased angiogenesis, increased Akt activity, decreased atrial natriuretic peptide gene expression, and maintenance of sarcoplasmic reticulum Ca(2+) ATPase gene expression. Improved outcome in LNA-antimiR-34-treated MI and TAC mice was accompanied by up-regulation of several direct miR-34 targets, including vascular endothelial growth factors, vinculin, protein O-fucosyltranferase 1, Notch1, and semaphorin 4B. Our results provide evidence that silencing of the entire miR-34 family can protect the heart against pathological cardiac remodeling and improve function. Furthermore, these data underscore the utility of seed-targeting 8-mer LNA-antimiRs in the development of new therapeutic approaches for pharmacologic inhibition of disease-implicated miRNA seed families.
Authors:
Bianca C Bernardo; Xiao-Ming Gao; Catherine E Winbanks; Esther J H Boey; Yow Keat Tham; Helen Kiriazis; Paul Gregorevic; Susanna Obad; Sakari Kauppinen; Xiao-Jun Du; Ruby C Y Lin; Julie R McMullen
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-10-09
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  109     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-24     Completed Date:  2013-01-07     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  17615-20     Citation Subset:  IM    
Affiliation:
Baker IDI Heart and Diabetes Institute, Melbourne, VIC 8008, Australia.
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MeSH Terms
Descriptor/Qualifier:
Animals
Base Sequence
DNA
DNA-Binding Proteins / metabolism
Fucosyltransferases / metabolism
Heart Function Tests*
Mice
MicroRNAs / antagonists & inhibitors*
Molecular Sequence Data
Neovascularization, Pathologic
Oligonucleotides / chemistry
Semaphorins / metabolism
Up-Regulation
Ventricular Remodeling*
Vinculin / metabolism
Chemical
Reg. No./Substance:
0/Bcl6 protein, mouse; 0/DNA-Binding Proteins; 0/MIRN34 microRNA, mouse; 0/MicroRNAs; 0/Oligonucleotides; 0/Semaphorins; 0/locked nucleic acid; 0/semaphorin 4B, mouse; 125361-02-6/Vinculin; 9007-49-2/DNA; EC 2.4.1.-/Fucosyltransferases; EC 2.4.1.221/Pofut1 protein, mouse
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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