Show simple item record

dc.contributor.authorMarcus, Frank I
dc.date.accessioned2019-09-05T02:02:28Z
dc.date.available2019-09-05T02:02:28Z
dc.date.issued2019-07-02
dc.identifier.citationJ Clin Invest. 2019;129(8):3171–3184. https://doi.org/10.1172/JCI125538.en_US
dc.identifier.issn0021-9738
dc.identifier.pmid31264976
dc.identifier.doi10.1172/JCI125538
dc.identifier.urihttp://hdl.handle.net/10150/634080
dc.description.abstractArrhythmogenic cardiomyopathy (ACM) is an inherited arrhythmia syndrome characterized by severe structural and electrical cardiac phenotypes, including myocardial fibrofatty replacement and sudden cardiac death. Clinical management of ACM is largely palliative, owing to an absence of therapies that target its underlying pathophysiology, which stems partially from our limited insight into the condition. Following identification of deceased ACM probands possessing ANK2 rare variants and evidence of ankyrin-B loss of function on cardiac tissue analysis, an ANK2 mouse model was found to develop dramatic structural abnormalities reflective of human ACM, including biventricular dilation, reduced ejection fraction, cardiac fibrosis, and premature death. Desmosomal structure and function appeared preserved in diseased human and murine specimens in the presence of markedly abnormal beta-catenin expression and patterning, leading to identification of a previously unknown interaction between ankyrin-B and beta-catenin. A pharmacological activator of the WNT/beta-catenin pathway, SB-216763, successfully prevented and partially reversed the murine ACM phenotypes. Our findings introduce what we believe to be a new pathway for ACM, a role of ankyrin-B in cardiac structure and signaling, a molecular link between ankyrin-B and beta-catenin, and evidence for targeted activation of the WNT/beta-catenin pathway as a potential treatment for this disease.en_US
dc.description.sponsorshipMarianne Barrie Philanthropic Fund; Canadian Institutes of Health Research [RN332805]; Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation; Dutch Federation of University Medical Centers; Netherlands Organisation for Health Research and Development; Royal Netherlands Academy of Sciences [CVON-PREDICT 2012-10]; Netherlands Cardiovascular Research Initiative - Dutch Heart Foundation [CVON2012-10 PREDICT CVON2018-30 PREDICT2, CVON2015-12 eDETECT]; Netherlands Organization for Scientific Research (NWO) [040.11.586]; Fondation Leducq [16 CVD 02]; Dr. Francis P. Chiramonte Private Foundation; Leyla Erkan Family Fund for ARVD Research; Robin Shah ARVD Fund at Johns Hopkins; Bogle Foundation; Healing Hearts Foundation; Campanella Family; Patrick J. Harrison Family; Peter French Memorial Foundation; Wilmerding Endowments; NIH [HL135754, HL134824, HL139348, HL135096, HL114383, HL114893, HL137331, HL137325, 2UM1HG006542, UL1 TR 001079]; Ohio State Frick Center; JB Projecten_US
dc.language.isoenen_US
dc.publisherAMER SOC CLINICAL INVESTIGATION INCen_US
dc.rightsCopyright © 2019. American Society for Clinical Investigation.en_US
dc.titleAnkyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapyen_US
dc.typeArticleen_US
dc.contributor.departmentUniv Arizona, Div Cardiol, Sarver Heart Ctren_US
dc.identifier.journalJOURNAL OF CLINICAL INVESTIGATIONen_US
dc.description.noteOpen access journalen_US
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.en_US
dc.eprint.versionFinal published versionen_US
dc.source.journaltitleThe Journal of clinical investigation
refterms.dateFOA2019-09-05T02:02:29Z


Files in this item

Thumbnail
Name:
125538.2-20190731115256-covere ...
Size:
20.02Mb
Format:
PDF
Description:
Final Published Version

This item appears in the following Collection(s)

Show simple item record