Document Detail


Sustaining cardiac claudin-5 levels prevents functional hallmarks of cardiomyopathy in a muscular dystrophy mouse model.
MedLine Citation:
PMID:  22547149     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Identification of new molecular targets in heart failure could ultimately have a substantial positive impact on both the health and financial aspects of treating the large heart failure population. We originally identified reduced levels of the cell junction protein claudin-5 specifically in heart in the dystrophin/utrophin-deficient (Dmd(mdx);Utrn(-/-)) mouse model of muscular dystrophy and cardiomyopathy, which demonstrates physiological hallmarks of heart failure. We then showed that at least 60% of cardiac explant samples from patients with heart failure resulting from diverse etiologies also have reduced claudin-5 levels. These claudin-5 reductions were independent of changes in other cell junction proteins previously linked to heart failure. The goal of this study was to determine whether sustaining claudin-5 levels is sufficient to prevent the onset of histological and functional indicators of heart failure. Here, we show the proof-of-concept rescue experiment in the Dmd(mdx);Utrn(-/-) model, in which claudin-5 reductions were originally identified. Expression of claudin-5 4 weeks after a single administration of recombinant adeno-associated virus (rAAV) containing a claudin-5 expression cassette prevented the onset of physiological hallmarks of cardiomyopathy and improved histological signs of cardiac damage. This experiment demonstrates that claudin-5 may represent a novel treatment target for prevention of heart failure.
Authors:
Dawn A Delfín; Ying Xu; Kevin E Schill; Tessily A Mays; Benjamin D Canan; Kara E Zang; Jamie A Barnum; Paul M L Janssen; Jill A Rafael-Fortney
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-05-01
Journal Detail:
Title:  Molecular therapy : the journal of the American Society of Gene Therapy     Volume:  20     ISSN:  1525-0024     ISO Abbreviation:  Mol. Ther.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-07-04     Completed Date:  2013-01-16     Revised Date:  2013-07-02    
Medline Journal Info:
Nlm Unique ID:  100890581     Medline TA:  Mol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1378-83     Citation Subset:  IM    
Affiliation:
Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cardiomyopathies / prevention & control*
Claudin-5 / genetics*,  metabolism*
Dependovirus / genetics
Disease Models, Animal
Dystrophin / genetics
Gene Transfer Techniques
Heart Failure / genetics,  prevention & control*
Mice
Mice, Inbred C57BL
Mice, Transgenic
Muscular Dystrophy, Animal / genetics,  metabolism*
Myocardium / metabolism*
Utrophin / deficiency,  genetics,  metabolism
Grant Support
ID/Acronym/Agency:
T32 HL098039/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Claudin-5; 0/Cldn5 protein, mouse; 0/Dystrophin; 0/Utrn protein, mouse; 0/Utrophin; 0/apo-dystrophin 1
Comments/Corrections

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