Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy
| Autor: | Paul M.L. Janssen, Jeff S. Healey, Nara Sobriera, Hugh Calkins, Samantha L. Simmons, Sharon L. Graw, Peter J. Mohler, Mona El-Refaey, Robert W. Davies, Brittney Murray, Danna A. Spears, Kirti Mittal, Duy T. Nguyen, Jason D. Roberts, Crystal Tichnell, Maarten P. van den Berg, J. Peter van Tintelen, Nathaniel P. Murphy, Sara N. Koenig, Daniel P. Judge, Philip C. Ursell, Meriam Åström Aneq, Mei Han, Crystal F. Kline, Robert A. Hegele, Anna Gréen, Luisa Mestroni, Andrew D. Krahn, Robert M. Hamilton, Amy C. Sturm, Arthur A.M. Wilde, Babak Nazer, Frank I. Marcus, Gianfranco Sinagra, Michael H. Gollob, Alberto Codima, David A. Chiasson, Chantal J. M. van Opbergen, Matthew R.G. Taylor, Shabana Aafaqi, Cynthia A. James, Edgar T. Hoorntje, Martin J. Gardner, Tamara T. Koopmann, Ellen R. Lubbers, Meena Fatah, Anthony Tang, Hassan Musa, Muhammad Rafiq, Loren E. Wold, Allan C. Skanes, Thomas J. Hund, John F. Robinson, Melvin M. Scheinman, Elisabeth M. Lodder, Toon A.B. van Veen |
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| Přispěvatelé: | Roberts, J. D., Murphy, N. P., Hamilton, R. M., Lubbers, E. R., James, C. A., Kline, C. F., Gollob, M. H., Krahn, A. D., Sturm, A. C., Musa, H., El-Refaey, M., Koenig, S., Aneq, M. A., Hoorntje, E. T., Graw, S. L., Davies, R. W., Rafiq, M. A., Koopmann, T. T., Aafaqi, S., Fatah, M., Chiasson, D. A., Taylor, M. R. G., Simmons, S. L., Han, M., Van Opbergen, C. J. M., Wold, L. E., Sinagra, G., Mittal, K., Tichnell, C., Murray, B., Codima, A., Nazer, B., Nguyen, D. T., Marcus, F. I., Sobriera, N., Lodder, E. M., Van Den Berg, M. P., Spears, D. A., Robinson, J. F., Ursell, P. C., Green, A. K., Skanes, A. C., Tang, A. S., Gardner, M. J., Hegele, R. A., Van Veen, T. A. B., Wilde, A. A. M., Healey, J. S., Janssen, P. M. L., Mestroni, L., Van Tintelen, J. P., Calkins, H., Judge, D. P., Hund, T. J., Scheinman, M. M., Mohler, P. J., Cardiovascular Centre (CVC), Cardiology, Human Genetics, ACS - Heart failure & arrhythmias |
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Indoles Cardiac fibrosis Cell- och molekylärbiologi Cardiomyopathy Arrhythmias Cardiovascular Medical and Health Sciences Sudden cardiac death Maleimides Mice 0302 clinical medicine 2.1 Biological and endogenous factors Aetiology Wnt Signaling Pathway Arrhythmogenic Right Ventricular Dysplasia beta Catenin Mice Knockout Ejection fraction Cardiology Cardiovascular disease Cell Biology Genetic diseases Wnt signaling pathway General Medicine Phenotype 3. Good health Heart Disease 030220 oncology & carcinogenesis Female Arrhythmia Research Article Ankyrins Knockout Immunology 03 medical and health sciences Rare Diseases Clinical Research ANK2 Journal Article medicine Animals Humans Loss function Animal business.industry Myocardium medicine.disease Disease Models Animal 030104 developmental biology Disease Models Cancer research business Cell and Molecular Biology |
| Zdroj: | Journal of Clinical Investigation, 129(8), 3171. The American Society for Clinical Investigation The Journal of Clinical Investigation, 129(8), 3171-3184. AMER SOC CLINICAL INVESTIGATION INC Journal of clinical investigation, 130, 3171-3184. The American Society for Clinical Investigation The Journal of clinical investigation, vol 129, iss 8 |
| ISSN: | 1558-8238 0021-9738 |
| DOI: | 10.1172/jci125538 |
| Popis: | Arrhythmogenic 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. Funding Agencies|Marianne 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 Project |
| Databáze: | OpenAIRE |
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