Transcriptional Dysregulation Underlies Both Monogenic Arrhythmia Syndrome and Common Modifiers of Cardiac Repolarization.

Autor: Bersell KR; Departments of Pharmacology (K.R.B., A.M.G., D.O.K., K.K., J-E.S., C.C.C., Q.S.W., S.P., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN., Yang T; Medicine (T.Y., J.D.M., J.D.B., J-E.S., Q.S.W., L.S., M.A.B., C.S., T.J.W., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN., Mosley JD; Departments of Pharmacology (K.R.B., A.M.G., D.O.K., K.K., J-E.S., C.C.C., Q.S.W., S.P., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN., Glazer AM; Departments of Pharmacology (K.R.B., A.M.G., D.O.K., K.K., J-E.S., C.C.C., Q.S.W., S.P., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN., Hale AT; Biochemistry (A.T.H., J.D.Y.), Vanderbilt University, Nashville, TN., Kryshtal DO; Departments of Pharmacology (K.R.B., A.M.G., D.O.K., K.K., J-E.S., C.C.C., Q.S.W., S.P., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN., Kim K; Departments of Pharmacology (K.R.B., A.M.G., D.O.K., K.K., J-E.S., C.C.C., Q.S.W., S.P., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN., Steimle JD; Departments of Pediatrics, Pathology, and Human Genetics, University of Chicago, IL (J.D.S., I.P.M.)., Brown JD; Medicine (T.Y., J.D.M., J.D.B., J-E.S., Q.S.W., L.S., M.A.B., C.S., T.J.W., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN., Salem JE; Departments of Pharmacology (K.R.B., A.M.G., D.O.K., K.K., J-E.S., C.C.C., Q.S.W., S.P., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN.; Medicine (T.Y., J.D.M., J.D.B., J-E.S., Q.S.W., L.S., M.A.B., C.S., T.J.W., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN.; Assistance Publique - Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Department of Pharmacology, CIC-1901, Sorbonne University, Paris, France (J-E.S.).; Sorbonne Universités, UPMC Univ Paris 06, Faculty of Medicine, France (J-E.S.)., Campbell CC; Departments of Pharmacology (K.R.B., A.M.G., D.O.K., K.K., J-E.S., C.C.C., Q.S.W., S.P., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN., Hong CC; Department of Medicine, University of Maryland School of Medicine, Baltimore (C.C.H.)., Wells QS; Departments of Pharmacology (K.R.B., A.M.G., D.O.K., K.K., J-E.S., C.C.C., Q.S.W., S.P., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN.; Medicine (T.Y., J.D.M., J.D.B., J-E.S., Q.S.W., L.S., M.A.B., C.S., T.J.W., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN.; Biomedical Informatics (Q.S.W., D.M.R.), Vanderbilt University, Nashville, TN., Johnson AN; Molecular Physiology and Biophysics (A.N.J.), Vanderbilt University, Nashville, TN., Short L; Medicine (T.Y., J.D.M., J.D.B., J-E.S., Q.S.W., L.S., M.A.B., C.S., T.J.W., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN., Blair MA; Medicine (T.Y., J.D.M., J.D.B., J-E.S., Q.S.W., L.S., M.A.B., C.S., T.J.W., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN., Behr ER, Petropoulou E; Cardiology Clinical Academic Group, Molecular and Clinical Sciences Institute, St George's, University of London and St George's University Hospitals National Health Service Foundation Trust, London, UK (E.P., Y.J.)., Jamshidi Y; Cardiology Clinical Academic Group, Molecular and Clinical Sciences Institute, St George's, University of London and St George's University Hospitals National Health Service Foundation Trust, London, UK (E.P., Y.J.)., Benson MD; Cardiovascular Research Center (E.J.B., M.D.B., M.J.K., R.E.G.), Beth Israel Deaconess Hospital, Boston, MA.; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (M.D.B.)., Keyes MJ; Cardiovascular Research Center (E.J.B., M.D.B., M.J.K., R.E.G.), Beth Israel Deaconess Hospital, Boston, MA., Ngo D; Division of Pulmonary and Cardiovascular Medicine (D.N., R.E.G.), Beth Israel Deaconess Hospital, Boston, MA., Vasan RS; Boston University School of Medicine, MA (R.S.V., Q.Y.)., Yang Q; Boston University School of Medicine, MA (R.S.V., Q.Y.)., Gerszten RE; Cardiovascular Research Center (E.J.B., M.D.B., M.J.K., R.E.G.), Beth Israel Deaconess Hospital, Boston, MA.; Division of Pulmonary and Cardiovascular Medicine (D.N., R.E.G.), Beth Israel Deaconess Hospital, Boston, MA., Shaffer C; Medicine (T.Y., J.D.M., J.D.B., J-E.S., Q.S.W., L.S., M.A.B., C.S., T.J.W., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN., Parikh S; Departments of Pharmacology (K.R.B., A.M.G., D.O.K., K.K., J-E.S., C.C.C., Q.S.W., S.P., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN., Sheng Q, Kannankeril PJ; Pediatrics (P.J.K.), Vanderbilt University, Nashville, TN., Moskowitz IP; Departments of Pediatrics, Pathology, and Human Genetics, University of Chicago, IL (J.D.S., I.P.M.)., York JD; Biochemistry (A.T.H., J.D.Y.), Vanderbilt University, Nashville, TN., Wang TJ; Medicine (T.Y., J.D.M., J.D.B., J-E.S., Q.S.W., L.S., M.A.B., C.S., T.J.W., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN., Knollmann BC; Departments of Pharmacology (K.R.B., A.M.G., D.O.K., K.K., J-E.S., C.C.C., Q.S.W., S.P., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN.; Medicine (T.Y., J.D.M., J.D.B., J-E.S., Q.S.W., L.S., M.A.B., C.S., T.J.W., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN., Roden DM; Departments of Pharmacology (K.R.B., A.M.G., D.O.K., K.K., J-E.S., C.C.C., Q.S.W., S.P., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN.; Medicine (T.Y., J.D.M., J.D.B., J-E.S., Q.S.W., L.S., M.A.B., C.S., T.J.W., B.C.K., D.M.R.), Vanderbilt University, Nashville, TN.; Biomedical Informatics (Q.S.W., D.M.R.), Vanderbilt University, Nashville, TN.
Jazyk: angličtina
Zdroj: Circulation [Circulation] 2023 Mar 07; Vol. 147 (10), pp. 824-840. Date of Electronic Publication: 2022 Dec 16.
DOI: 10.1161/CIRCULATIONAHA.122.062193
Abstrakt: Background: Brugada syndrome (BrS) is an inherited arrhythmia syndrome caused by loss-of-function variants in the cardiac sodium channel gene SCN5A (sodium voltage-gated channel alpha subunit 5) in ≈20% of subjects. We identified a family with 4 individuals diagnosed with BrS harboring the rare G145R missense variant in the cardiac transcription factor TBX5 (T-box transcription factor 5) and no SCN5A variant.
Methods: We generated induced pluripotent stem cells (iPSCs) from 2 members of a family carrying TBX5-G145R and diagnosed with Brugada syndrome. After differentiation to iPSC-derived cardiomyocytes (iPSC-CMs), electrophysiologic characteristics were assessed by voltage- and current-clamp experiments (n=9 to 21 cells per group) and transcriptional differences by RNA sequencing (n=3 samples per group), and compared with iPSC-CMs in which G145R was corrected by CRISPR/Cas9 approaches. The role of platelet-derived growth factor (PDGF)/phosphoinositide 3-kinase (PI3K) pathway was elucidated by small molecule perturbation. The rate-corrected QT (QTc) interval association with serum PDGF was tested in the Framingham Heart Study cohort (n=1893 individuals).
Results: TBX5-G145R reduced transcriptional activity and caused multiple electrophysiologic abnormalities, including decreased peak and enhanced "late" cardiac sodium current (I Na ), which were entirely corrected by editing G145R to wild-type. Transcriptional profiling and functional assays in genome-unedited and -edited iPSC-CMs showed direct SCN5A down-regulation caused decreased peak I Na , and that reduced PDGF receptor ( PDGFRA [platelet-derived growth factor receptor α]) expression and blunted signal transduction to PI3K was implicated in enhanced late I Na . Tbx5 regulation of the PDGF axis increased arrhythmia risk due to disruption of PDGF signaling and was conserved in murine model systems. PDGF receptor blockade markedly prolonged normal iPSC-CM action potentials and plasma levels of PDGF in the Framingham Heart Study were inversely correlated with the QTc interval ( P <0.001).
Conclusions: These results not only establish decreased SCN5A transcription by the TBX5 variant as a cause of BrS, but also reveal a new general transcriptional mechanism of arrhythmogenesis of enhanced late sodium current caused by reduced PDGF receptor-mediated PI3K signaling.
Databáze: MEDLINE
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