학술논문
Impact of stress on cardiac phenotypes in mice harboring an ankyrin-B disease variant.
Document Type
Academic Journal
Author
Wallace MJ; The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA; Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio, USA.; Malhotra N; The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA; Department of Surgery/Division of Cardiac Surgery, The Ohio State University, Columbus, Ohio, USA.; Mariángelo JIE; The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA; Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio, USA.; Stevens TL; The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA; Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio, USA.; Young LJ; The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA.; Antwi-Boasiako S; The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA.; Abdallah D; The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA.; Takenaka SS; The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA.; Cavus O; The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA.; Murphy NP; The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA.; Han M; The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA.; Xu X; The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA.; Mangoni ME; Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France.; Hund TJ; The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA; Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, Ohio, USA; Department of Internal Medicine/Division of Cardiovascular Medicine, The Ohio State University, Columbus, Ohio, USA.; Roberts JD; Population Health Research Institute, McMaster University, and Hamilton Health Sciences, Hamilton, Ontario, Canada.; Györke S; The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA; Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio, USA.; Mohler PJ; The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA; Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio, USA; Department of Internal Medicine/Division of Cardiovascular Medicine, The Ohio State University, Columbus, Ohio, USA.; El Refaey M; The Frick Center for Heart Failure and Arrhythmia, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA; Department of Surgery/Division of Cardiac Surgery, The Ohio State University, Columbus, Ohio, USA. Electronic address: Mona.elrefaey@osumc.edu.
Source
Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE
Subject
Language
English
Abstract
Encoded by ANK2, ankyrin-B (AnkB) is a multifunctional adapter protein critical for the expression and targeting of key cardiac ion channels, transporters, cytoskeletal-associated proteins, and signaling molecules. Mice deficient for AnkB expression are neonatal lethal, and mice heterozygous for AnkB expression display cardiac structural and electrical phenotypes. Human ANK2 loss-of-function variants are associated with diverse cardiac manifestations; however, human clinical 'AnkB syndrome' displays incomplete penetrance. To date, animal models for human arrhythmias have generally been knock-out or transgenic overexpression models and thus the direct impact of ANK2 variants on cardiac structure and function in vivo is not clearly defined. Here, we directly tested the relationship of a single human ANK2 disease-associated variant with cardiac phenotypes utilizing a novel in vivo animal model. At baseline, young AnkBp.E1458G +/+ mice lacked significant structural or electrical abnormalities. However, aged AnkBp.E1458G +/+ mice displayed both electrical and structural phenotypes at baseline including bradycardia and aberrant heart rate variability, structural remodeling, and fibrosis. Young and old AnkBp.E1458G +/+ mice displayed ventricular arrhythmias following acute (adrenergic) stress. In addition, young AnkBp.E1458G +/+ mice displayed structural remodeling following chronic (transverse aortic constriction) stress. Finally, AnkBp.E1458G +/+ myocytes harbored alterations in expression and/or localization of key AnkB-associated partners, consistent with the underlying disease mechanism. In summary, our findings illustrate the critical role of AnkB in in vivo cardiac function as well as the impact of single AnkB loss-of-function variants in vivo. However, our findings illustrate the contribution and in fact necessity of secondary factors (aging, adrenergic challenge, pressure-overload) to phenotype penetrance and severity.
Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.
(Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.
(Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)