Key result
TGF-β1 stimulation drives a more inflammatory phenotype and greater inflammasome activation in RV versus LV fibroblasts.
Why the study?
Intrinsic differences between left and right ventricular fibroblasts and their responses to TGF-beta1 have not yet been investigated.
Right ventricular fibroblasts exhibit a more inflammatory phenotype in response to pro-fibrotic stimuli compared to left ventricular fibroblasts, highlighting intrinsic differences in ventricular remodeling.
May require RV-specific anti-inflammatory therapy in HF; extends LV fibroblast research to chamber-specific remodeling.
Background Heart failure is a syndrome that not solely affects the left ventricle (LV), but also the right ventricle (RV). Distinct differences between the two ventricles, including variations in inflammation and remodelling processes have been observed in heart failure. We previously have shown how transforming growth factor (TGF)-ß1 influences LV fibroblast activation and the attraction of pro- and anti-inflammatory monocyte subsets. However, the intrinsic differences between LV and RV fibroblasts, as well as their distinct responses to TGF-β1, have not yet been investigated. Purpose The study aimed to investigate the differences in the fibro-inflammatory potential of LV- and RV-derived fibroblasts towards a common pro-fibrotic trigger. Methods Primary fibroblasts were obtained from the LV and RV of male C57BL6/j mice by outgrowth culture. Cells were stimulated with TGF-β1 (5 ng/mL) for up to 72h to examine mRNA expression, chemokine release, cell migration, and inflammasome activation. Results In both LV and RV fibroblasts, TGF-ß1 induced myofibroblast differentiation, as indicated by higher collagen I, III, α-smooth muscle actin (α-SMA), lysyl oxidase (Lox)-1 and lysyl oxidase-like (LoxL)-2 mRNA expression levels compared to controls. This was paralleled by higher soluble collagen and Lox protein levels in the cell culture supernatant of the TGF-ß1-stimulated groups versus the respective control groups. Furthermore, both LV and RV fibroblasts stimulated with TGF-β1 displayed a higher CC-chemokine ligand (CCL) 2, CCL7, and chemokine C-X3-C motif ligand (Cx3CL1) release compared to control fibroblasts. Surprisingly, RV fibroblasts stimulated with TGF-β1 exhibited lower Lox protein levels compared to their LV counterparts. Subsequent analysis of monocyte migration towards the conditioned media revealed higher Ly6Chigh/Ly6Clow monocyte ratio in TGF-β1-stimulated RV fibroblasts compared to the corresponding LV-conditioned media, indicative for a more inflammatory phenotype. Additional examination of inflammasome activation revealed higher numbers of NOD-like receptor family, pyrin domain containing (Nlrp) 3+, apoptosis-associated speck-like protein containing a CARD domain (ASC)+, and interleukin (IL)-1β+ RV fibroblast compared to LV fibroblasts under control and TGF-β1 conditions. Conclusion LV and RV fibroblasts differ in their responsiveness towards pro-fibrotic stimuli, suggesting fundamental differences in remodelling under disease conditions.
No takes yet. Share an insight, caveat, or question.
Pappritz et al. (2026) studied this question. RV fibroblasts exhibited a more inflammatory phenotype and greater inflammasome activation compared to LV fibroblasts when stimulated with TGF-β1.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: