title: Loss of αT-catenin alters the hybrid adhering junctions in the heart and leads to dilated cardiomyopathy and ventricular arrhythmia following acute ischemia.
abstract: It is generally accepted that the intercalated disc (ICD) required for mechano-electrical coupling in the heart consists of three distinct junctional complexes: adherens junctions, desmosomes and gap junctions. However, recent morphological and molecular data indicate a mixing of adherens junctional and desmosomal components, resulting in a 'hybrid adhering junction' or 'area composita'. The α-catenin family member αT-catenin, part of the N-cadherin-catenin adhesion complex in the heart, is the only α-catenin that interacts with the desmosomal protein plakophilin-2 (PKP2). Thus, it has been postulated that αT-catenin might serve as a molecular integrator of the two adhesion complexes in the area composita. To investigate the role of αT-catenin in the heart, gene targeting technology was used to delete the Ctnna3 gene, encoding αT-catenin, in the mouse. The αT-catenin-null mice are viable and fertile; however, the animals exhibit progressive cardiomyopathy. Adherens junctional and desmosomal proteins were unaffected by loss of αT-catenin, with the exception of the desmosomal protein PKP2. Immunogold labeling at the ICD demonstrated in the αT-catenin-null heart a preferential reduction of PKP2 at the area composita compared with the desmosome. Furthermore, gap junction protein Cx43 was reduced at the ICD, including its colocalization with N-cadherin. Gap junction remodeling in αT-catenin-knockout hearts was associated with an increased incidence of ventricular arrhythmias after acute ischemia. This novel animal model demonstrates for the first time how perturbation in αT-catenin can affect both PKP2 and Cx43 and thereby highlights the importance of understanding the crosstalk between the junctional proteins of the ICD and its implications for arrhythmogenic cardiomyopathy.
authors.affiliation: Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA,  USA.
authors.forename: Jifen
authors.initials: J
authors.lastname: Li
authors.forename: Steven
authors.initials: S
authors.lastname: Goossens
authors.forename: Jolanda
authors.initials: J
authors.lastname: van Hengel
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.forename: Lan
authors.initials: L
authors.lastname: Cheng
authors.forename: Koen
authors.initials: K
authors.lastname: Tyberghein
authors.forename: Xiying
authors.initials: X
authors.lastname: Shang
authors.forename: Riet
authors.initials: R
authors.lastname: De Rycke
authors.forename: Frans
authors.initials: F
authors.lastname: van Roy
authors.forename: Glenn L
authors.initials: GL
authors.lastname: Radice
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D015820:Cadherins / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology; D018031:Connexin 43 / Q000172:deficiency / Q000378:metabolism; D003896:Desmosomes / Q000378:metabolism; D004195:Disease Models, Animal; D004562:Electrocardiography; D017629:Gap Junctions / Q000378:metabolism* / Q000473:pathology; D006352:Heart Ventricles / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D017202:Myocardial Ischemia / Q000150:complications*; D015428:Myocardial Reperfusion Injury; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D051191:Plakophilins / Q000172:deficiency / Q000378:metabolism; D051178:alpha Catenin / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
chemical_list: C575065:CTNNA3 protein, mouse; D015820:Cadherins; D018031:Connexin 43; C495338:Pkp2 protein, mouse; D051191:Plakophilins; D051178:alpha Catenin