Engineered cardiac tissue model of restrictive cardiomyopathy for drug discovery.

Autor:	Wang BZ; Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA., Nash TR; Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA., Zhang X; Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York, NY 10032, USA., Rao J; Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York, NY 10032, USA., Abriola L; Yale Center for Molecular Discovery, Yale University, New Haven, CT 06520, USA., Kim Y; Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA., Zakharov S; Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York, NY 10032, USA., Kim M; Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York, NY 10032, USA., Luo LJ; Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA., Morsink M; Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA., Liu B; Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA., Lock RI; Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA., Fleischer S; Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA., Tamargo MA; Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA., Bohnen M; Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York, NY 10032, USA., Welch CL; Department of Pediatrics, Columbia University, New York, NY 10032, USA., Chung WK; Department of Pediatrics, Columbia University, New York, NY 10032, USA., Marx SO; Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York, NY 10032, USA., Surovtseva YV; Yale Center for Molecular Discovery, Yale University, New Haven, CT 06520, USA., Vunjak-Novakovic G; Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA; Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York, NY 10032, USA; College of Dental Medicine, Columbia University, New York, NY 10032, USA., Fine BM; Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: barry.fine@columbia.edu.
Jazyk:	angličtina
Zdroj:	Cell reports. Medicine [Cell Rep Med] 2023 Mar 21; Vol. 4 (3), pp. 100976. Date of Electronic Publication: 2023 Mar 14.
DOI:	10.1016/j.xcrm.2023.100976
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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