title: Sarcomeric lesions and remodeling proximal to intercalated disks in overload-induced cardiac hypertrophy.
abstract: Pressure overload induces cardiac remodeling involving both the contractile machinery and intercalated disks (IDs). Filamin C (FlnC) and Xin actin-binding repeat-containing proteins (XIRPs) are multi-adapters localizing in IDs of higher vertebrates. Knockout of the gene encoding Xin (Xirp1) in mice leads to a mild cardiac phenotype with ID mislocalization. In order to amplify this phenotype, we performed transverse aortic constriction (TAC) on control and Xirp1-deficient mice. TAC induced similar left ventricular hypertrophy in both genotypes, suggesting that the lack of Xin does not lead to higher susceptibility to cardiac overload. However, in both genotypes, FlnC appeared in "streaming" localizations across multiple sarcomeres proximal to the IDs, suggesting a remodeling response. Furthermore, FlnC-positive areas of remodeling, reminiscent of sarcomeric lesions previously described for skeletal muscles (but so far unreported in the heart), were also observed. These adaptations reflect a similarly strong effect of the pressure induced by TAC in both genotypes. However, 2 weeks post-operation TAC-treated knockout hearts had reduced levels of connexin43 and slightly increased incidents of ventricular tachycardia compared to their wild-type (WT) counterparts. Our findings highlight the FlnC-positive sarcomeric lesions and ID-proximal streaming as general remodeling responses in cardiac overload-induced hypertrophy.
authors.affiliation: Institute of Physiology II, University Hospital Bonn, Nussallee 11, 53115 Bonn, Germany. Electronic address: Sied.Kebir@ukb.uni-bonn.de.
authors.forename: Sied
authors.initials: S
authors.lastname: Kebir
authors.affiliation: Institute for Cell Biology, Department of Molecular Cell Biology, University of Bonn, Ulrich-Haberland-Str. 61a, 53121 Bonn, Germany. Electronic address: orfanos@uni-bonn.de.
authors.forename: Zacharias
authors.initials: Z
authors.lastname: Orfanos
authors.affiliation: Institute for Cell Biology, Department of Molecular Cell Biology, University of Bonn, Ulrich-Haberland-Str. 61a, 53121 Bonn, Germany. Electronic address: julis@uni-bonn.de.
authors.forename: Julia
authors.initials: J
authors.lastname: Schuld
authors.affiliation: Department of Medicine-Cardiology, University of Bonn Medical Center, Sigmund-Freud-Straße 25, 53127 Bonn, Germany. Electronic address: Markus.Linhart@ukb.uni-bonn.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Linhart
authors.affiliation: Institute for Cell Biology, Department of Molecular Cell Biology, University of Bonn, Ulrich-Haberland-Str. 61a, 53121 Bonn, Germany. Electronic address: christian.lamberz@dzne.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Lamberz
authors.affiliation: Institute for Cell Biology, Department of Molecular Cell Biology, University of Bonn, Ulrich-Haberland-Str. 61a, 53121 Bonn, Germany. Electronic address: pvdven@uni-bonn.de.
authors.forename: Peter F M
authors.initials: PF
authors.lastname: van der Ven
authors.affiliation: Department of Medicine-Cardiology, University of Bonn Medical Center, Sigmund-Freud-Straße 25, 53127 Bonn, Germany. Electronic address: Jan.Schrickel@ukb.uni-bonn.de.
authors.forename: Jan
authors.initials: J
authors.lastname: Schrickel
authors.affiliation: Institute for Cell Biology, Department of Molecular Cell Biology, University of Bonn, Ulrich-Haberland-Str. 61a, 53121 Bonn, Germany. Electronic address: g.kirfel@uni-bonn.de.
authors.forename: Gregor
authors.initials: G
authors.lastname: Kirfel
authors.affiliation: Institute for Cell Biology, Department of Molecular Cell Biology, University of Bonn, Ulrich-Haberland-Str. 61a, 53121 Bonn, Germany. Electronic address: dfuerst@uni-bonn.de.
authors.forename: Dieter O
authors.initials: DO
authors.lastname: Fürst
authors.affiliation: Institute of Physiology II, University Hospital Bonn, Nussallee 11, 53115 Bonn, Germany. Electronic address: rainer.meyer@ukb.uni-bonn.de.
authors.forename: Rainer
authors.initials: R
authors.lastname: Meyer
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D001145:Arrhythmias, Cardiac / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology; D006332:Cardiomegaly / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology*; D018031:Connexin 43 / Q000378:metabolism; D003251:Constriction, Pathologic; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism; D004562:Electrocardiography; D005260:Female; D064448:Filamins / Q000378:metabolism; D017379:Hypertrophy, Left Ventricular / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology; D051379:Mice; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000172:deficiency / Q000378:metabolism; D010641:Phenotype; D012518:Sarcomeres / Q000473:pathology*; D013610:Tachycardia / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology
chemical_list: D018031:Connexin 43; D004268:DNA-Binding Proteins; D064448:Filamins; D009687:Nuclear Proteins; C118478:Xin protein, mouse
keywords: Connexin43; Cross-striated muscle cells; Filamin C; XIRP2; Xin actin-binding repeat-containing proteins; Xirp1