Claudin-5 levels are reduced from multiple cell types in human failing hearts and are associated with mislocalization of ephrin-B1

Swager, Sarah A.; Delfín, Dawn A.; Rastogi, Neha; Wang, Honglan; Canan, Benjamin D.; Fedorov, Vadim V.; Mohler, Peter J.; Kilic, Ahmet; Higgins, Robert S.D.; Ziolo, Mark T.; Janssen, Paul M. L.; Rafael‐Fortney, Jill A.

doi:10.1016/j.carpath.2014.10.006

Cited by 18 publications

(21 citation statements)

References 26 publications

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“…Claudin-5, which has been identified as the major integral membrane protein and primary seal of the TJs1920, represents an early marker of endothelial dysfunction in different pathological conditions2122. Here, with the aim of assessing whether the perturbed gene expression of TJPs (Fig.…”

Section: Resultsmentioning

confidence: 99%

Impairment of blood-brain barrier is an early event in R6/2 mouse model of Huntington Disease

Pardo

Amico

Scalabrì

et al. 2017

Sci Rep

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Blood-brain barrier (BBB) breakdown, due to the concomitant disruption of the tight junctions (TJs), normally required for the maintenance of BBB function, and to the altered transport of molecules between blood and brain and vice-versa, has been suggested to significantly contribute to the development and progression of different brain disorders including Huntington’s disease (HD). Although the detrimental consequence the BBB breakdown may have in the clinical settings, the timing of its alteration remains elusive for many neurodegenerative diseases. In this study we demonstrate for the first time that BBB disruption in HD is not confined to established symptoms, but occurs early in the disease progression. Despite the obvious signs of impaired BBB permeability were only detectable in concomitance with the onset of the disease, signs of deranged TJs integrity occur precociously in the disease and precede the onset of overt symptoms. To our perspective this finding may add a new dimension to the horizons of pathological mechanisms underlying this devastating disease, however much remains to be elucidated for understanding how specific BBB drug targets can be approached in the future.

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Section: Resultsmentioning

confidence: 99%

Impairment of blood-brain barrier is an early event in R6/2 mouse model of Huntington Disease

Pardo

Amico

Scalabrì

et al. 2017

Sci Rep

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“…Combined, the seemingly normal levels of claudin-5 combined with the significant levels on non-myocyte claudin-5 expression unfortunately prevents detection of small or even modest changes in myocyte-localized claudin-5 in Sgcd −/− myocardium. We have previously demonstrated that claudin-5 protein is reduced in the majority of end-stage human heart failure samples (Mays et al, 2008; Swager et al, 2015). Claudin-5 has also been shown in an unbiased screen to be one of only four genes down-regulated and hyper-methylated in human dilated cardiomyopathy (Koczor et al, 2013).…”

Section: Discussionmentioning

confidence: 95%

“…Therefore, it is likely, as we have no other explanation for the improved function, that detectable claudin-5 reductions may occur at a later time-point than studied here in Sgcd −/− mice and only minor, undetectable increases were able to sustain myocardial contractile force at the time-point in this study. Claudin-5 localizes to the lateral membranes of cardiomyocytes where the DGC resides (Swager et al, 2015), and may be able to partially compensate for the lost DGC connection that normally acts to protect this membrane in striated muscles. Higher resolution localization studies would be required to determine whether exogenous claudin-5 is present in membrane micro-domains typically occupied by the DGC.…”

Section: Discussionmentioning

confidence: 99%

Myocardial Contractile Dysfunction Is Present without Histopathology in a Mouse Model of Limb-Girdle Muscular Dystrophy-2F and Is Prevented after Claudin-5 Virotherapy

et al. 2016

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Mutations in several members of the dystrophin glycoprotein complex lead to skeletal and cardiomyopathies. Cardiac care for these muscular dystrophies consists of management of symptoms with standard heart medications after detection of reduced whole heart function. Recent evidence from both Duchenne muscular dystrophy patients and animal models suggests that myocardial dysfunction is present before myocardial damage or deficiencies in whole heart function, and that treatment prior to heart failure symptoms may be beneficial. To determine whether this same early myocardial dysfunction is present in other muscular dystrophy cardiomyopathies, we conducted a physiological assessment of cardiac function at the tissue level in the δ-sarcoglycan null mouse model (Sgcd−/−) of Limb-girdle muscular dystrophy type 2F. Baseline cardiac contractile force measurements using ex vivo intact linear muscle preparations, were severely depressed in these mice without the presence of histopathology. Virotherapy withclaudin-5 prevents the onset of cardiomyopathy in another muscular dystrophy model. After virotherapy with claudin-5, the cardiac contractile force deficits in Sgcd−/− mice are no longer significant. These studies suggest that screening Limb-girdle muscular dystrophy patients using methods that detect earlier functional changes may provide a longer therapeutic window for cardiac care.

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“…That is, they possessed positive force–frequency relationship and a robust response to beta-adrenergic stimulation [17]. Finally, studies on overall histopathology and specific protein levels and localization support that the nonfailing hearts show significantly reduced pathology compared to failing hearts [18]. …”

Section: Methodsmentioning

confidence: 99%

Altered protein levels in the isolated extracellular matrix of failing human hearts with dilated cardiomyopathy

DeAguero

McKown

Zhang

et al. 2017

Cardiovascular Pathology

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Dilated cardiomyopathy (DCM) is associated with extensive pathological cardiac remodeling and involves numerous changes in the protein expression profile of the extracellular matrix of the heart. We obtained seven human, end-stage, failing hearts with DCM (DCM-failing) and nine human, nonfailing donor hearts and compared their extracellular matrix protein profiles. We first showed that the DCM-failing hearts had indeed undergone extensive remodeling of the left ventricle myocardium relative to nonfailing hearts. We then isolated the extracellular matrix from a subset of these hearts and performed a proteomic analysis on the isolated matrices. We found that the levels of 26 structural proteins were altered in the DCM-failing isolated cardiac extracellular matrix compared to nonfailing isolated cardiac extracellular matrix. Overall, most of the extracellular matrix proteins showed reduced levels in the DCM-failing hearts, while all of the contractile proteins showed increased levels. There was a mixture of increased and decreased levels of cytoskeletal and nuclear transport proteins. Using immunoprobing, we verified that collagen IV (α2 and α6 isoforms), zyxin, and myomesin protein levels were reduced in the DCM-failing hearts. We expect that these data will add to the understanding of the pathology associated with heart failure with DCM.

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Claudin-5 levels are reduced from multiple cell types in human failing hearts and are associated with mislocalization of ephrin-B1

Cited by 18 publications

References 26 publications

Impairment of blood-brain barrier is an early event in R6/2 mouse model of Huntington Disease

Impairment of blood-brain barrier is an early event in R6/2 mouse model of Huntington Disease

Myocardial Contractile Dysfunction Is Present without Histopathology in a Mouse Model of Limb-Girdle Muscular Dystrophy-2F and Is Prevented after Claudin-5 Virotherapy

Altered protein levels in the isolated extracellular matrix of failing human hearts with dilated cardiomyopathy

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