Engineered cardiac tissue model of restrictive cardiomyopathy for drug discovery
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved..
Restrictive cardiomyopathy (RCM) is defined as increased myocardial stiffness and impaired diastolic relaxation leading to elevated ventricular filling pressures. Human variants in filamin C (FLNC) are linked to a variety of cardiomyopathies, and in this study, we investigate an in-frame deletion (c.7416_7418delGAA, p.Glu2472_Asn2473delinAsp) in a patient with RCM. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) with this variant display impaired relaxation and reduced calcium kinetics in 2D culture when compared with a CRISPR-Cas9-corrected isogenic control line. Similarly, mutant engineered cardiac tissues (ECTs) demonstrate increased passive tension and impaired relaxation velocity compared with isogenic controls. High-throughput small-molecule screening identifies phosphodiesterase 3 (PDE3) inhibition by trequinsin as a potential therapy to improve cardiomyocyte relaxation in this genotype. Together, these data demonstrate an engineered cardiac tissue model of RCM and establish the translational potential of this precision medicine approach to identify therapeutics targeting myocardial relaxation.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:4 |
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| Enthalten in: |
Cell reports. Medicine - 4(2023), 3 vom: 21. März, Seite 100976 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wang, Bryan Z [VerfasserIn] |
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| Links: |
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| Themen: |
FLNC |
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| Anmerkungen: |
Date Completed 24.03.2023 Date Revised 13.02.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.xcrm.2023.100976 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM35427127X |
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| 245 | 1 | 0 | |a Engineered cardiac tissue model of restrictive cardiomyopathy for drug discovery |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a Restrictive cardiomyopathy (RCM) is defined as increased myocardial stiffness and impaired diastolic relaxation leading to elevated ventricular filling pressures. Human variants in filamin C (FLNC) are linked to a variety of cardiomyopathies, and in this study, we investigate an in-frame deletion (c.7416_7418delGAA, p.Glu2472_Asn2473delinAsp) in a patient with RCM. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) with this variant display impaired relaxation and reduced calcium kinetics in 2D culture when compared with a CRISPR-Cas9-corrected isogenic control line. Similarly, mutant engineered cardiac tissues (ECTs) demonstrate increased passive tension and impaired relaxation velocity compared with isogenic controls. High-throughput small-molecule screening identifies phosphodiesterase 3 (PDE3) inhibition by trequinsin as a potential therapy to improve cardiomyocyte relaxation in this genotype. Together, these data demonstrate an engineered cardiac tissue model of RCM and establish the translational potential of this precision medicine approach to identify therapeutics targeting myocardial relaxation | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
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| 650 | 4 | |a high throughput drug screen | |
| 650 | 4 | |a induced pluripotent stem cell | |
| 650 | 4 | |a restrictive cardiomyopathy | |
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| 700 | 1 | |a Nash, Trevor R |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xiaokan |e verfasserin |4 aut | |
| 700 | 1 | |a Rao, Jenny |e verfasserin |4 aut | |
| 700 | 1 | |a Abriola, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Youngbin |e verfasserin |4 aut | |
| 700 | 1 | |a Zakharov, Sergey |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Luo, Lori J |e verfasserin |4 aut | |
| 700 | 1 | |a Morsink, Margaretha |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Bohao |e verfasserin |4 aut | |
| 700 | 1 | |a Lock, Roberta I |e verfasserin |4 aut | |
| 700 | 1 | |a Fleischer, Sharon |e verfasserin |4 aut | |
| 700 | 1 | |a Tamargo, Manuel A |e verfasserin |4 aut | |
| 700 | 1 | |a Bohnen, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Welch, Carrie L |e verfasserin |4 aut | |
| 700 | 1 | |a Chung, Wendy K |e verfasserin |4 aut | |
| 700 | 1 | |a Marx, Steven O |e verfasserin |4 aut | |
| 700 | 1 | |a Surovtseva, Yulia V |e verfasserin |4 aut | |
| 700 | 1 | |a Vunjak-Novakovic, Gordana |e verfasserin |4 aut | |
| 700 | 1 | |a Fine, Barry M |e verfasserin |4 aut | |
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