| Sustaining cardiac claudin-5 levels prevents functional hallmarks of cardiomyopathy in a muscular dystrophy mouse model. | |
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MedLine Citation:
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PMID: 22547149 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-05-01 |
Journal Detail:
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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:
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Created Date: 2012-07-04 Completed Date: 2013-01-16 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 100890581 Medline TA: Mol Ther Country: United States |
Other Details:
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Languages: eng Pagination: 1378-83 Citation Subset: IM |
Affiliation:
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Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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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:
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T32 HL098039/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Claudin-5; 0/Cldn5 protein, mouse; 0/Dystrophin; 0/Utrn protein, mouse; 0/Utrophin; 0/apo-dystrophin 1 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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