ArticleThe Journal of clinical investigation2025
Cardiac fibroblast BAG3 regulates TGFBR2 signaling and fibrosis in dilated cardiomyopathy.
Article in The Journal of clinical investigation, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Article
- The ubiquitin system in heart and vessel pathobiology: From mechanisms to therapeutic strategies.Genes & diseases · 2026Review
- Multiple triggering mechanisms of myocardial fibrosis: Comparison and integration in different disease contexts.iScience · 2026Review
- A practical toolbox for modelling fibrosis in vitro.Nature biomedical engineering · 2026Review
- Review
- Deletion of Murine Endothelial <italic>Bag3</italic> Alters the Cellular Proteome among Organs of Origin.Journal of vascular research · 2026Article
- Cardiomyocyte programmed cell death in dilated cardiomyopathy: molecular crosstalk and therapeutic implications.Frontiers in cell and developmental biology · 2026Review
- Signals from the extracellular matrix: Region- and sex-specificity in cardiac aging.Current opinion in cell biology · 2025Review
- The BAG3-HSP70-CHIP axis controls the degradation of TGFBR2 in cardiac fibroblasts.Journal of molecular and cellular cardiology · 2025Article
- Cardiac Fibroblasts: Helping or Hurting.Genes · 2025Review
- Ubiquitin-specific protease: an emerging key player in cardiomyopathy.Cell communication and signaling : CCS · 2025Review
- Article
- A patient-specific engineered tissue model of BAG3-mediated cardiomyopathy.Journal of tissue engineeringArticle
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Authors and funding
24 authors.
Funding
Abstract
Loss of Bcl2-associated athanogene 3 (BAG3) is associated with dilated cardiomyopathy (DCM). BAG3 regulates sarcomere protein turnover in cardiomyocytes; however, the function of BAG3 in other cardiac cell types is understudied. In this study, we used an isogenic pair of BAG3-knockout and wild-type human induced pluripotent stem cells (hiPSCs) to interrogate the role of BAG3 in hiPSC-derived cardiac fibroblasts (CFs). Analysis of cell type-specific conditional knockout engineered heart tissues revealed an essential contribution of CF BAG3 to contractility and cardiac fibrosis, recapitulating the phenotype of DCM. In BAG3-/- CFs, we observed an increased sensitivity to TGF-β signaling and activation of a fibrogenic response when cultured at physiological stiffness (8 kPa). Mechanistically, we showed that loss of BAG3 increased transforming growth factor-β receptor 2 (TGFBR2) levels by directly binding TGFBR2 and mediating its ubiquitination and proteasomal degradation. To further validate these results, we performed single-nucleus RNA sequencing of cardiac tissue from DCM patients carrying pathogenic BAG3 variants. BAG3 pathogenic variants increased fibrotic gene expression in CFs. Together, these results extend our understanding of the roles of BAG3 in heart disease beyond the cardiomyocyte-centric view and highlight the ability of tissue-engineered hiPSC models to elucidate cell type-specific aspects of cardiac disease.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.