title: Sustaining cardiac claudin-5 levels prevents functional hallmarks of cardiomyopathy in a muscular dystrophy mouse model.
abstract: 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.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Dawn A
authors.initials: DA
authors.lastname: Delfín
authors.forename: Ying
authors.initials: Y
authors.lastname: Xu
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Schill
authors.forename: Tessily A
authors.initials: TA
authors.lastname: Mays
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Canan
authors.forename: Kara E
authors.initials: KE
authors.lastname: Zang
authors.forename: Jamie A
authors.initials: JA
authors.lastname: Barnum
authors.forename: Paul M L
authors.initials: PM
authors.lastname: Janssen
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rafael-Fortney
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000517:prevention & control*; D062507:Claudin-5 / Q000235:genetics* / Q000378:metabolism*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D016189:Dystrophin / Q000235:genetics; D018014:Gene Transfer Techniques; D006333:Heart Failure / Q000235:genetics / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D049411:Utrophin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D062507:Claudin-5; C491511:Cldn5 protein, mouse; D016189:Dystrophin; C483600:Utrn protein, mouse; D049411:Utrophin; C085339:apo-dystrophin 1