Loss of BAG3 in cardiac fibroblasts increased TGFBR2 levels and sensitivity to TGF-β signaling, leading to a fibrogenic response and reduced contractility that recapitulates dilated cardiomyopathy.
Does loss of BAG3 in cardiac fibroblasts increase TGF-β signaling and fibrosis in dilated cardiomyopathy models?
Loss of BAG3 in cardiac fibroblasts contributes to dilated cardiomyopathy by increasing TGFBR2 levels and promoting a fibrogenic response, highlighting a non-cardiomyocyte mechanism in BAG3-related heart disease.
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.
Wang et al. (Wed,) conducted a other in Dilated cardiomyopathy. BAG3 knockout and pathogenic variants vs. Wild-type BAG3 was evaluated on Contractility, cardiac fibrosis, and TGFBR2 signaling. Loss of BAG3 in cardiac fibroblasts increased TGFBR2 levels and sensitivity to TGF-β signaling, leading to a fibrogenic response and reduced contractility that recapitulates dilated cardiomyopathy.