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Citations to this article

Investigation of a dilated cardiomyopathy–associated variant in BAG3 using genome-edited iPSC-derived cardiomyocytes
Chris McDermott-Roe, … , Aron Geurts, Kiran Musunuru
Chris McDermott-Roe, … , Aron Geurts, Kiran Musunuru
Published November 14, 2019
Citation Information: JCI Insight. 2019;4(22):e128799. https://doi.org/10.1172/jci.insight.128799.
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Research Article Cardiology Genetics

Investigation of a dilated cardiomyopathy–associated variant in BAG3 using genome-edited iPSC-derived cardiomyocytes

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Abstract

Mutations in B cell lymphoma 2–associated athanogene 3 (BAG3) are recurrently associated with dilated cardiomyopathy (DCM) and muscular dystrophy. Using isogenic genome-edited human induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs), we examined how a DCM-causing BAG3 mutation (R477H), as well as complete loss of BAG3 (KO), impacts myofibrillar organization and chaperone networks. Although unchanged at baseline, fiber length and alignment declined markedly in R477H and KO iPSC-CMs following proteasome inhibition. RNA sequencing revealed extensive baseline changes in chaperone- and stress response protein–encoding genes, and protein levels of key BAG3 binding partners were perturbed. Molecular dynamics simulations of the BAG3-HSC70 complex predicted a partial disengagement by the R477H mutation. In line with this, BAG3-R477H bound less HSC70 than BAG3-WT in coimmunoprecipitation assays. Finally, myofibrillar disarray triggered by proteasome inhibition in R477H cells was mitigated by overexpression of the stress response protein heat shock factor 1 (HSF1). These studies reveal the importance of BAG3 in coordinating protein quality control subsystem usage within the cardiomyocyte and suggest that augmenting HSF1 activity might be beneficial as a means to mitigate proteostatic stress in the context of BAG3-associated DCM.

Authors

Chris McDermott-Roe, Wenjian Lv, Tania Maximova, Shogo Wada, John Bukowy, Maribel Marquez, Shuping Lai, Amarda Shehu, Ivor Benjamin, Aron Geurts, Kiran Musunuru

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Year: 2025 2024 2023 2022 2021 2020 Total
Citations: 1 2 7 5 11 6 32
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Citations to this article (32)

Title and authors Publication Year
Induced Pluripotent Stem Cells in Cardiomyopathy: Advancing Disease Modeling, Therapeutic Development, and Regenerative Therapy
Vo QD, Nakamura K, Saito Y, Akagi S, Miyoshi T, Yuasa S
International Journal of Molecular Sciences 2025
Current Status of Cardiac Regenerative Therapy Using Induced Pluripotent Stem Cells
Sugiura T, Shahannaz DC, Ferrell BE
International journal of molecular sciences 2024
Integrating Prime Editing and Cellular Reprogramming as Novel Strategies for Genetic Cardiac Disease Modeling and Treatment.
Yao B, Lei Z, Gonçalves MAFV, Sluijter JPG
Current cardiology reports 2024
Cardiac calcium regulation in human induced pluripotent stem cell cardiomyocytes: Implications for disease modeling and maturation
Ernst P, Bidwell PA, Dora M, Thomas DD, Kamdar F
Frontiers in Cell and Developmental Biology 2023
Functional genomics in stroke: current and future applications of iPSCs and gene editing to dissect the function of risk variants
Granata A
BMC Cardiovascular Disorders 2023
Transcriptome studies of inherited dilated cardiomyopathies.
Koslow M, Mondaca-Ruff D, Xu X
Mammalian genome : official journal of the International Mammalian Genome Society 2023
Bag3 Regulates Mitochondrial Function and the Inflammasome Through Canonical and Noncanonical Pathways in the Heart
Wang J, Tomar D, Martin TG, Dubey S, Dubey PK, Song J, Landesberg G, McCormick MG, Myers VD, Merali S, Merali C, Lemster B, McTiernan CF, Khalili K, Madesh M, Cheung JY, Kirk JA, Feldman AM
JACC: Basic to Translational Science 2023
Dysregulated Autophagy and Sarcomere Dysfunction in Patients With Heart Failure With Co‐Occurrence of P63A and P380S BAG3 Variants
Martin TG, Pak H, Gerhard GS, Merali S, Merali C, Lemster B, Dubey P, McTiernan CF, Bristow MR, Feldman AM, Kirk JA
Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease 2023
Harnessing human genetics and stem cells for precision cardiovascular medicine
Caudal A, Snyder MP, Wu JC
2023
Two Cases of Myofibrillar Myopathies: Genetic and Quality of Life Study
Angelini C, Ceolin C, Rodriguez AA, Nigro V
Muscles 2023
Modeling Nonischemic Genetic Cardiomyopathies Using Induced Pluripotent Stem Cells.
Khedro T, Duran JM, Adler ED
Current Cardiology Reports 2022
CRISPR Modeling and Correction of Cardiovascular Disease
Liu N, Olson EN
Circulation research 2022
Inhibitors of the Ubiquitin Proteasome System block myofibril assembly in cardiomyocytes derived from chick embryos and human pluripotent stem cells
Wang J, Fan Y, Wang C, Dube S, Poiesz BJ, Dube DK, Ma Z, Sanger JM, Sanger JW
Cytoskeleton (Hoboken, N.J.) 2022
Machine learning and bioinformatics to identify 8 autophagy-related biomarkers and construct gene regulatory networks in dilated cardiomyopathy.
Zhang F, Xia M, Jiang J, Wang S, Zhao Q, Yu C, Yu J, Xian D, Li X, Zhang L, Liu Y, Peng M
Scientific Reports 2022
Serine biosynthesis as a novel therapeutic target for dilated cardiomyopathy
Perea-Gil I, Seeger T, Bruyneel AA, Termglinchan V, Monte E, Lim EW, Vadgama N, Furihata T, Gavidia AA, Arthur Ataam J, Bharucha N, Martinez-Amador N, Ameen M, Nair P, Serrano R, Kaur B, Feyen DA, Diecke S, Snyder MP, Metallo CM, Mercola M, Karakikes I
European Heart Journal 2022
Therapeutic targeting of BAG3: Considering its complexity in cancer and heart disease
Jonathan Kirk, Joseph Cheung, Arthur Feldman
Journal of Clinical Investigation 2021
Hsp22 Deficiency Induces Age-Dependent Cardiac Dilation and Dysfunction by Impairing Autophagy, Metabolism, and Oxidative Response
W Wu, X Sun, X Shi, L Lai, C Wang, M Xie, G Qin, H Qiu
Antioxidants 2021
With or without You: Co-Chaperones Mediate Health and Disease by Modifying Chaperone Function and Protein Triage
S Altinok, R Sanchez-Hodge, M Stewart, K Smith, JC Schisler
Cells 2021
Human iPSCs and Genome Editing Technologies for Precision Cardiovascular Tissue Engineering
EK Gähwiler, SE Motta, M Martin, B Nugraha, SP Hoerstrup, MY Emmert
Frontiers in Cell and Developmental Biology 2021
The role of BAG3 in health and disease: A “Magic BAG of Tricks”
H Lin, SA Koren, G Cvetojevic, P Girardi, GV Johnson
Journal of Cellular Biochemistry 2021
Genetic Cardiomyopathies: The Lesson Learned from hiPSCs
I My, ED Pasquale
Journal of Clinical Medicine 2021
Uncovering Inherited Cardiomyopathy With Human Induced Pluripotent Stem Cells
X Jiang, Y Chen, X Liu, L Ye, M Yu, Z Shen, W Lei, S Hu
Frontiers in Cell and Developmental Biology 2021
Dynamic effects of genetic variation on gene expression revealed following hypoxic stress in cardiomyocytes
MC Ward, NE Banovich, A Sarkar, M Stephens, Y Gilad
eLife 2021
Modulation of muscle redox and protein aggregation rescues lethality caused by mutant lamins
GS Coombs, JL Rios-Monterrosa, S Lai, Q Dai, AC Goll, MR Ketterer, MF Valdes, N Uche, IJ Benjamin, LL Wallrath
Redox Biology 2021
BAG3-related myofibrillar myopathy: a further observation with cardiomyopathy at onset in pediatric age
Gaia Scarpini, Maria Lucia Valentino, Melania Giannotta, Luca Ragni, Annalaura Torella, Marta Columbaro, Vincenzo Nigro, Antonella Pini
Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology 2021
Chronic ethanol exposure induces deleterious changes in cardiomyocytes derived from human induced pluripotent stem cells
Liu R, Sun F, Armand LC, Wu R, Xu C
Stem Cell Reviews and Reports 2021
Negative chronotropic and inotropic effects of lubiprostone on iPS cell-derived cardiomyocytes via activation of CFTR
H Akita, S Yoshie, T Ishida, Y Takeishi, A Hazama
2020
Genome Editing for the Understanding and Treatment of Inherited Cardiomyopathies
Nguyen, Lim, Yokota
International journal of molecular sciences 2020
Come Together: Protein Assemblies, Aggregates and the Sarcostat at the Heart of Cardiac Myocyte Homeostasis
M Islam, A Diwan, K Mani
Frontiers in physiology 2020
Modeling Cardiac Disease Mechanisms Using Induced Pluripotent Stem Cell-Derived Cardiomyocytes: Progress, Promises and Challenges
EI Parrotta, V Lucchino, L Scaramuzzino, S Scalise, G Cuda
International journal of molecular sciences 2020
Human Induced Pluripotent Stem Cells as a Disease Model System for Heart Failure
A Deicher, T Seeger
Current Heart Failure Reports 2020
Modeling Cardiovascular Diseases with hiPSC-Derived Cardiomyocytes in 2D and 3D Cultures
C Sacchetto, L Vitiello, LJ de Windt, A Rampazzo, M Calore
International journal of molecular sciences 2020

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