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  Junctophilin-2 expression rescues atrial dysfunction through polyadic junctional membrane complex biogenesis.

Brandenburg, S., Pawlowitz, J., Eikenbusch, B., Peper, J., Kohl, T., Mitronova, G., et al. (2019). Junctophilin-2 expression rescues atrial dysfunction through polyadic junctional membrane complex biogenesis. JCI Insight, 4(12): e127116. doi:10.1172/jci.insight.127116.

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Brandenburg, S., Autor
Pawlowitz, J., Autor
Eikenbusch, B., Autor
Peper, J., Autor
Kohl, T., Autor
Mitronova, G.1, Autor           
Sossalla, S., Autor
Hasenfuss, G., Autor
Wehrens, X. H. T., Autor
Kohl, P., Autor
Rog-Zielinska, E. A., Autor
Lehnart, S. E., Autor
Affiliations:
1Department of NanoBiophotonics, MPI for biophysical chemistry, Max Planck Society, ou_578627              

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 Zusammenfassung: Atrial dysfunction is highly prevalent and associated with increased severity of heart failure. While rapid excitation-contraction coupling depends on axial junctions in atrial myocytes, the molecular basis of atrial loss of function remains unclear. We identified approximately 5-fold lower junctophilin-2 levels in atrial compared with ventricular tissue in mouse and human hearts. In atrial myocytes, this resulted in subcellular expression of large junctophilin-2 clusters at axial junctions, together with highly phosphorylated ryanodine receptor (RyR2) channels. To investigate the contribution of junctophilin-2 to atrial pathology in adult hearts, we developed a cardiomyocyte-selective junctophilin-2-knockdown model with 0 mortality. Junctophilin-2 knockdown in mice disrupted atrial RyR2 clustering and contractility without hypertrophy or interstitial fibrosis. In contrast, aortic pressure overload resulted in left atrial hypertrophy with decreased junctophilin-2 and RyR2 expression, disrupted axial junctions, and atrial fibrosis. Whereas pressure overload accrued atrial dysfunction and heart failure with 40% mortality, additional junctophilin-2 knockdown greatly exacerbated atrial dysfunction with 100% mortality. Strikingly, transgenic junctophilin-2 overexpression restored atrial contractility and survival through de novo biogenesis of polyadic junctional membrane complexes maintained after pressure overload. Our data show a central role of junctophilin-2 cluster disruption in atrial hypertrophy and identify transgenic augmentation of junctophilin-2 as a disease-mitigating rationale to improve atrial dysfunction and prevent heart failure deterioration.

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Sprache(n): eng - English
 Datum: 2019-06-20
 Publikationsstatus: Online veröffentlicht
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 Art der Begutachtung: Expertenbegutachtung
 Identifikatoren: DOI: 10.1172/jci.insight.127116
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Titel: JCI Insight
Genre der Quelle: Zeitschrift
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Seiten: 22 Band / Heft: 4 (12) Artikelnummer: e127116 Start- / Endseite: - Identifikator: -