دورية أكاديمية
أعرض في EDS

Metastable Atrial State Underlies the Primary Genetic Substrate for MYL4 Mutation-Associated Atrial Fibrillation.

التفاصيل البيبلوغرافية
العنوان: Metastable Atrial State Underlies the Primary Genetic Substrate for MYL4 Mutation-Associated Atrial Fibrillation.
المؤلفون: Ghazizadeh Z; Cardiovascular Medicine Division (Z.G., T.K., S.O., D.P., M.E.B., K.Z., L.G., A.A.W., S.K., C.A.M.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA., Kiviniemi T; Cardiovascular Medicine Division (Z.G., T.K., S.O., D.P., M.E.B., K.Z., L.G., A.A.W., S.K., C.A.M.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.; Heart Center, Turku University Hospital (T.K., A.E., J.G., J.A.), Harvard T.H.; University of Turku, Finland (T.K., A.E., J.G., J.A.). Harvard T.H., Olafsson S; Cardiovascular Medicine Division (Z.G., T.K., S.O., D.P., M.E.B., K.Z., L.G., A.A.W., S.K., C.A.M.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA., Plotnick D; Cardiovascular Medicine Division (Z.G., T.K., S.O., D.P., M.E.B., K.Z., L.G., A.A.W., S.K., C.A.M.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA., Beerens ME; Cardiovascular Medicine Division (Z.G., T.K., S.O., D.P., M.E.B., K.Z., L.G., A.A.W., S.K., C.A.M.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA., Zhang K; Cardiovascular Medicine Division (Z.G., T.K., S.O., D.P., M.E.B., K.Z., L.G., A.A.W., S.K., C.A.M.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA., Gillon L; Cardiovascular Medicine Division (Z.G., T.K., S.O., D.P., M.E.B., K.Z., L.G., A.A.W., S.K., C.A.M.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA., Steinbaugh MJ; Chan School of Public Health, Boston, MA (M.J.S., V.B., S.H.S.)., Barrera V; Chan School of Public Health, Boston, MA (M.J.S., V.B., S.H.S.)., Sui SH; Chan School of Public Health, Boston, MA (M.J.S., V.B., S.H.S.)., Werdich AA; Cardiovascular Medicine Division (Z.G., T.K., S.O., D.P., M.E.B., K.Z., L.G., A.A.W., S.K., C.A.M.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA., Kapur S; Cardiovascular Medicine Division (Z.G., T.K., S.O., D.P., M.E.B., K.Z., L.G., A.A.W., S.K., C.A.M.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA., Eranti A; Heart Center, Turku University Hospital (T.K., A.E., J.G., J.A.), Harvard T.H.; University of Turku, Finland (T.K., A.E., J.G., J.A.). Harvard T.H., Gunn J; Heart Center, Turku University Hospital (T.K., A.E., J.G., J.A.), Harvard T.H.; University of Turku, Finland (T.K., A.E., J.G., J.A.). Harvard T.H., Jalkanen J; Medicity Research Laboratories (J.J., M.H.), Harvard T.H., Airaksinen J; Heart Center, Turku University Hospital (T.K., A.E., J.G., J.A.), Harvard T.H.; University of Turku, Finland (T.K., A.E., J.G., J.A.). Harvard T.H., Kleber AG; Department of Pathology, Beth Israel Deaconess Medical Center Harvard Medical School, Boston, MA (A.G.K.)., Hollmén M; Medicity Research Laboratories (J.J., M.H.), Harvard T.H., MacRae CA; Cardiovascular Medicine Division (Z.G., T.K., S.O., D.P., M.E.B., K.Z., L.G., A.A.W., S.K., C.A.M.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.; Genetics and Network Medicine Divisions (C.A.M.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.; Harvard Stem Cell Institute, Boston, MA (C.A.M.).
المصدر: Circulation [Circulation] 2020 Jan 28; Vol. 141 (4), pp. 301-312. Date of Electronic Publication: 2019 Nov 16.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 0147763 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1524-4539 (Electronic) Linking ISSN: 00097322 NLM ISO Abbreviation: Circulation Subsets: MEDLINE
أسماء مطبوعة: Publication: Hagerstown, MD : Lippincott Williams & Wilkins
Original Publication: [Dallas, Tex., etc., American Heart Association, etc.]
مواضيع طبية MeSH: Atrial Fibrillation*/genetics , Atrial Fibrillation*/metabolism , Atrial Fibrillation*/pathology , Mutation* , Myocytes, Cardiac*/metabolism , Myocytes, Cardiac*/pathology , Myosin Light Chains*/genetics , Myosin Light Chains*/metabolism, Animals ; Animals, Genetically Modified/genetics ; Animals, Genetically Modified/metabolism ; Cell Line ; Connexin 43/genetics ; Connexin 43/metabolism ; Gene Knockout Techniques ; Heart Atria/metabolism ; Heart Atria/pathology ; Human Embryonic Stem Cells/metabolism ; Human Embryonic Stem Cells/pathology ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Induced Pluripotent Stem Cells/pathology ; Zebrafish ; Zebrafish Proteins/genetics ; Zebrafish Proteins/metabolism
مستخلص: Background: Atrial fibrillation (AF) is the most common clinical arrhythmia and is associated with heart failure, stroke, and increased mortality. The myocardial substrate for AF is poorly understood because of limited access to primary human tissue and mechanistic questions around existing in vitro or in vivo models.
Methods: Using an MYH6:mCherry knock-in reporter line, we developed a protocol to generate and highly purify human pluripotent stem cell-derived cardiomyocytes displaying physiological and molecular characteristics of atrial cells. We modeled human MYL4 mutants, one of the few definitive genetic causes of AF. To explore non-cell-autonomous components of AF substrate, we also created a zebrafish Myl4 knockout model, which exhibited molecular, cellular, and physiologic abnormalities that parallel those in humans bearing the cognate mutations.
Results: There was evidence of increased retinoic acid signaling in both human embryonic stem cells and zebrafish mutant models, as well as abnormal expression and localization of cytoskeletal proteins, and loss of intracellular nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide + hydrogen. To identify potentially druggable proximate mechanisms, we performed a chemical suppressor screen integrating multiple human cellular and zebrafish in vivo endpoints. This screen identified Cx43 (connexin 43) hemichannel blockade as a robust suppressor of the abnormal phenotypes in both models of MYL4 (myosin light chain 4)-related atrial cardiomyopathy. Immunofluorescence and coimmunoprecipitation studies revealed an interaction between MYL4 and Cx43 with altered localization of Cx43 hemichannels to the lateral membrane in MYL4 mutants, as well as in atrial biopsies from unselected forms of human AF. The membrane fraction from MYL4-/- human embryonic stem cell derived atrial cells demonstrated increased phospho-Cx43, which was further accentuated by retinoic acid treatment and by the presence of risk alleles at the Pitx2 locus. PKC (protein kinase C) was induced by retinoic acid, and PKC inhibition also rescued the abnormal phenotypes in the atrial cardiomyopathy models.
Conclusions: These data establish a mechanistic link between the transcriptional, metabolic and electrical pathways previously implicated in AF substrate and suggest novel avenues for the prevention or therapy of this common arrhythmia.
معلومات مُعتمدة: R00 HL112724 United States HL NHLBI NIH HHS
فهرسة مساهمة: Keywords: atrial fibrillation; connexin 43; human embryonic stem cells; myosin light chains; tretinoin
المشرفين على المادة: 0 (Connexin 43)
0 (MYL4 protein, human)
0 (Myosin Light Chains)
0 (Zebrafish Proteins)
تواريخ الأحداث: Date Created: 20191119 Date Completed: 20200630 Latest Revision: 20210311
رمز التحديث: 20221213
DOI: 10.1161/CIRCULATIONAHA.119.044268
PMID: 31735076
قاعدة البيانات: MEDLINE
الوصف
تدمد:1524-4539
DOI:10.1161/CIRCULATIONAHA.119.044268