Pro-inflammatory role of Wnt/β-catenin signaling in endothelial dysfunction

by Selleckchem | Aug 21 2023

Background: Endothelial dysfunction is a critical component of both atherosclerotic plaque formation and saphenous vein graft failure. Crosstalk between the pro-inflammatory TNF-α-NFκB signaling axis and the canonical Wnt/β-catenin signaling pathway potentially plays an important role in regulating endothelial dysfunction, though the exact nature of this is not defined.

Results: In this study, cultured endothelial cells were challenged with TNF-α and the potential of a Wnt/β-catenin signaling inhibitor, iCRT-14, in reversing the adverse effects of TNF-α on endothelial physiology was evaluated. Treatment with iCRT-14 lowered nuclear and total NFκB protein levels, as well as expression of NFκB target genes, IL-8 and MCP-1. Inhibition of β-catenin activity with iCRT-14 suppressed TNF-α-induced monocyte adhesion and decreased VCAM-1 protein levels. Treatment with iCRT-14 also restored endothelial barrier function and increased levels of ZO-1 and focal adhesion-associated phospho-paxillin (Tyr118). Interestingly, inhibition of β-catenin with iCRT-14 enhanced platelet adhesion in cultured TNF-α-stimulated endothelial cells and in an ex vivo human saphenous vein model, most likely via elevating levels of membrane-tethered vWF. Wound healing was moderately retarded by iCRT-14; hence, inhibition of Wnt/β-catenin signaling may interfere with re-endothelialisation in grafted saphenous vein conduits.

Conclusion: Inhibition of the Wnt/β-catenin signaling pathway with iCRT-14 significantly recovered normal endothelial function by decreasing inflammatory cytokine production, monocyte adhesion and endothelial permeability. However, treatment of cultured endothelial cells with iCRT-14 also exerted a pro-coagulatory and moderate anti-wound healing effect: these factors may affect the suitability of Wnt/β-catenin inhibition as a therapy for atherosclerosis and vein graft failure.

Comments:

The study described the evaluation of a Wnt/β-catenin signaling inhibitor, iCRT-14, in reversing the adverse effects of TNF-α on endothelial cells. The researchers investigated the crosstalk between the pro-inflammatory TNF-α-NFκB signaling axis and the canonical Wnt/β-catenin signaling pathway, which are potentially involved in regulating endothelial dysfunction.

The results of the study showed that treatment with iCRT-14 had several beneficial effects on endothelial physiology. It lowered the levels of nuclear and total NFκB protein, as well as the expression of NFκB target genes such as IL-8 and MCP-1. This suggests that inhibiting β-catenin activity with iCRT-14 can suppress the inflammatory response induced by TNF-α.

Furthermore, iCRT-14 treatment decreased monocyte adhesion and reduced VCAM-1 protein levels. VCAM-1 is involved in the recruitment of monocytes to the endothelium, and its reduction indicates a potential decrease in inflammation and atherogenic processes.

iCRT-14 also improved endothelial barrier function, as evidenced by the restoration of endothelial permeability and increased levels of ZO-1, which is a marker of tight junction integrity. Additionally, it increased the levels of phospho-paxillin (Tyr118), a protein associated with focal adhesions, which are important for cell adhesion and migration.

However, an interesting observation was that inhibition of β-catenin with iCRT-14 enhanced platelet adhesion in both cultured TNF-α-stimulated endothelial cells and an ex vivo human saphenous vein model. This effect was likely due to elevated levels of membrane-tethered von Willebrand factor (vWF), which promotes platelet adhesion and aggregation. This pro-coagulatory effect suggests that inhibiting the Wnt/β-catenin signaling pathway may have implications for thrombotic events.

Additionally, the study found that iCRT-14 treatment moderately retarded wound healing. This suggests that inhibiting Wnt/β-catenin signaling may interfere with the re-endothelialization process in grafted saphenous vein conduits, which could be problematic in the context of vein graft failure.

In conclusion, the inhibition of the Wnt/β-catenin signaling pathway with iCRT-14 showed promising results in recovering normal endothelial function by decreasing inflammatory cytokine production, monocyte adhesion, and endothelial permeability. However, it also exerted pro-coagulatory effects and had a moderate negative impact on wound healing. These findings suggest that while Wnt/β-catenin inhibition may have therapeutic potential for atherosclerosis and vein graft failure, the pro-coagulatory and anti-wound healing effects should be considered when assessing its suitability as a therapeutic approach. Further research is needed to fully understand the complex interplay between the TNF-α-NFκB and Wnt/β-catenin signaling pathways and their implications for endothelial dysfunction and cardiovascular disease.