Cardiac fibroblast BAG3 regulates TGFBR2 signaling and fibrosis in dilated cardiomyopathy
Dilated Cardiomyopathy
Cardiac Fibrosis
BAG3
Myocardial fibrosis
DOI:
10.1172/jci181630
Publication Date:
2025-01-01T19:00:42Z
AUTHORS (24)
ABSTRACT
Loss of Bcl2-associated athanogene 3 (BAG3) is associated with dilated cardiomyopathy (DCM). BAG3 regulates sarcomere protein turnover in cardiomyocytes; however, the function other cardiac cell types understudied. In this study, we used an isogenic pair BAG3-knockout and wild-type human induced pluripotent stem cells (hiPSCs) to interrogate role hiPSC-derived fibroblasts (CFs). Analysis type-specific conditional knockout engineered heart tissues revealed essential contribution CF contractility fibrosis, recapitulating phenotype DCM. BAG3-/- CFs, observed increased sensitivity TGF-β signaling activation a fibrogenic response when cultured at physiological stiffness (8 kPa). Mechanistically, showed that loss transforming growth factor-β receptor 2 (TGFBR2) levels by directly binding TGFBR2 mediating its ubiquitination proteasomal degradation. To further validate these results, performed single-nucleus RNA sequencing tissue from DCM patients carrying pathogenic variants. variants fibrotic gene expression CFs. Together, results extend our understanding roles disease beyond cardiomyocyte-centric view highlight ability tissue-engineered hiPSC models elucidate aspects disease.
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