Transcriptional Dysregulation Underlies Both Monogenic Arrhythmia Syndrome and Common Modifiers of Cardiac Repolarization-Reference-Cited by-同舟云学术

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

Published:2023-03-07 Issue:10 Volume:147 Page:824-840
ISSN:0009-7322
Container-title:Circulation
language:en
Short-container-title:Circulation

Author:

Bersell Kevin R.¹^ORCID,Yang Tao²,Mosley Jonathan D.¹^ORCID,Glazer Andrew M.¹^ORCID,Hale Andrew T.³,Kryshtal Dmytro O.¹^ORCID,Kim Kyungsoo¹^ORCID,Steimle Jeffrey D.⁴,Brown Jonathan D.²^ORCID,Salem Joe-Elie¹²⁵⁶^ORCID,Campbell Courtney C.¹,Hong Charles C.⁷^ORCID,Wells Quinn S.¹²⁸^ORCID,Johnson Amanda N.⁹^ORCID,Short Laura²,Blair Marcia A.²,Behr Elijah R.^ORCID,Petropoulou Evmorfia¹⁰,Jamshidi Yalda¹⁰^ORCID,Benson Mark D.¹¹¹²,Keyes Michelle J.¹¹^ORCID,Ngo Debby¹³^ORCID,Vasan Ramachandran S.¹⁴^ORCID,Yang Qiong¹⁴^ORCID,Gerszten Robert E.¹¹¹³^ORCID,Shaffer Christian²,Parikh Shan¹,Sheng Quanhu^ORCID,Kannankeril Prince J.¹⁵^ORCID,Moskowitz Ivan P.⁴^ORCID,York John D.³,Wang Thomas J.²^ORCID,Knollmann Bjorn C.¹²^ORCID,Roden Dan M.¹²⁸^ORCID

Affiliation:

1. 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.

2. 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.

3. Biochemistry (A.T.H., J.D.Y.), Vanderbilt University, Nashville, TN.

4. Departments of Pediatrics, Pathology, and Human Genetics, University of Chicago, IL (J.D.S., I.P.M.).

5. Assistance Publique - Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Department of Pharmacology, CIC-1901, Sorbonne University, Paris, France (J-E.S.).

6. Sorbonne Universités, UPMC Univ Paris 06, Faculty of Medicine, France (J-E.S.).

7. Department of Medicine, University of Maryland School of Medicine, Baltimore (C.C.H.).

8. Biomedical Informatics (Q.S.W., D.M.R.), Vanderbilt University, Nashville, TN.

9. Molecular Physiology and Biophysics (A.N.J.), Vanderbilt University, Nashville, TN.

10. 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.).

11. Cardiovascular Research Center (E.J.B., M.D.B., M.J.K., R.E.G.), Beth Israel Deaconess Hospital, Boston, MA.

12. Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, MA (M.D.B.).

13. Division of Pulmonary and Cardiovascular Medicine (D.N., R.E.G.), Beth Israel Deaconess Hospital, Boston, MA.

14. Boston University School of Medicine, MA (R.S.V., Q.Y.).

15. Pediatrics (P.J.K.), Vanderbilt University, Nashville, TN.

Abstract

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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

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