Brandenburg, Sören

[["dc.bibliographiccitation.issue","12"],["dc.bibliographiccitation.journal","JCI insight"],["dc.bibliographiccitation.volume","4"],["dc.contributor.author","Brandenburg, Sören"],["dc.contributor.author","Pawlowitz, Jan"],["dc.contributor.author","Eikenbusch, Benjamin"],["dc.contributor.author","Peper, Jonas"],["dc.contributor.author","Kohl, Tobias"],["dc.contributor.author","Mitronova, Gyuzel Y."],["dc.contributor.author","Sossalla, Samuel"],["dc.contributor.author","Hasenfuss, Gerd"],["dc.contributor.author","Wehrens, Xander H. T."],["dc.contributor.author","Kohl, Peter"],["dc.contributor.author","Rog-Zielinska, Eva A."],["dc.contributor.author","Lehnart, Stephan E."],["dc.date.accessioned","2019-08-06T12:16:10Z"],["dc.date.available","2019-08-06T12:16:10Z"],["dc.date.issued","2019"],["dc.description.abstract","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."],["dc.identifier.doi","10.1172/jci.insight.127116"],["dc.identifier.pmid","31217359"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/62314"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/267"],["dc.language.iso","en"],["dc.notes.status","final"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | A09: Lokale molekulare Nanodomänen-Regulation der kardialen Ryanodin-Rezeptor-Funktion"],["dc.relation","SFB 1002 | D01: Erholung aus der Herzinsuffizienz – Einfluss von Fibrose und Transkriptionssignatur"],["dc.relation","SFB 1002 | S01: In vivo und in vitro Krankheitsmodelle"],["dc.relation","SFB 1002 | S02: Hochauflösende Fluoreszenzmikroskopie und integrative Datenanalyse"],["dc.relation.eissn","2379-3708"],["dc.relation.issn","2379-3708"],["dc.relation.workinggroup","RG Brandenburg"],["dc.relation.workinggroup","RG Hasenfuß (Transition zur Herzinsuffizienz)"],["dc.relation.workinggroup","RG Lehnart (Cellular Biophysics and Translational Cardiology Section)"],["dc.relation.workinggroup","RG Sossalla (Kardiovaskuläre experimentelle Elektrophysiologie und Bildgebung)"],["dc.title","Junctophilin-2 expression rescues atrial dysfunction through polyadic junctional membrane complex biogenesis"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]