Endothelial fibrosis induced by suppressed STAT3 expression mediated by signaling involving the TGF-β1/ALK5/Smad pathway

Abstract

During systemic inflammatory pathologies, mediators of inflammation circulate in the bloodstream and interact with endothelial cells (ECs), resulting in endothelial dysfunction that maintains and enhances the pathological condition. Inflammatory mediators change the protein expression profile of ECs, which become activated fibroblasts via endothelial-to-mesenchymal transition. This process is characterized by downregulated endothelial proteins and strongly upregulated fibrotic-specific genes and extracellular matrix-forming proteins. The main inductor of endothelial fibrosis is transforming growth factor-β1 (TGF-β1), which acts through the TGF-β1/activin receptor-like kinase 5 (ALK5)/Smads intracellular signaling pathway. The signal transducer and activator of transcription 3 (STAT3) is also involved in fibrosis in several tissues (e.g. heart and vascular system), where STAT3 signaling decreases TGF-β1-induced responses by directly interacting with Smad proteins, suggesting that decreased STAT3 could induce TGF-β1-mediated fibrosis. However, it is unknown if suppressed STAT3 expression induces EC fibrosis through a mechanism involving the TGF-β signaling pathway. The present study evaluated the fibrotic actions of STAT3 suppression in ECs and investigated TGF-β1/ALK5/Smad4 signaling pathway participation. Suppressed STAT3 expression stimulated fibrotic conversion in ECs, as mediated by protein expression reprograming that decreased endothelial marker expression and increased fibrotic and extracellular matrix protein levels. The potential mechanism underlying these changes was dependent on TGF-β1 secretion, the ALK5 activation pathway, and Smad4 translocation into the nucleus. We conclude that suppressed STAT3 expression converts ECs into activated fibroblasts via TGF-β1/ALK5/Smad4 signaling pathway involvement.

Endotoxemia-induced endothelial fibrosis inhibition improves hypotension, tachycardia, multiple organ dysfunction syndrome, cytokine response, oxidative stress, and survival

“…Endotoxininduced TGF-β isoform generation requires binding the TGF-β receptor type II (TβRII), which recruits TβRI or activin receptor-like kinase 5 (ALK5). Subsequently, ALK5 phosphorylates smad-2/3, which then binds smad-4 to regulate target gene transcription and promote fibrosis [25,32,34,35]. Thus, endotoxin-induced endothelial fibrosis is completely dependent on TGF-β secretion and ALK5 activation.…”

Epigenetic regulation of integrin β6 transcription induced by TGF‐β1 in human oral squamous cell carcinoma cells

“…Apart from JunB, transcription factor STAT3 has been shown to be involved in the positive regulation of ITGB6 basic transcription in OSCC cells, prostate, and breast epithelial cells . However, recent study presented that STAT3 signaling decreases TGF‐β1‐induced responses . We speculate that STAT3 may not be required for TGF‐β1‐induced ITGB6 transcription.…”

Idiopathic Pulmonary Fibrosis Serum proteomic analysis before and after nintedanib therapy

“…In turn, HPT and STAT3 interaction signaling is involved in the development of fibrosis and in the regulation of fibroblast senescence [14][15][16] . Interestingly, it has been demonstrated that the inhibition and activation of STAT3 are both related to the fibrosis onset following the cross-talk between STAT3 and TGF-β signaling, that is organ and tissue-dependent 17 . HPT could also be induced by the interaction of FGFR and VEGFR with CREB-binding protein (CBP), which is involved in cell growth, transformation and development and also shows histone acetyltransferase activity 18 .…”

“…5). The proteins of Group B (light blue bars) were associated with "liver regeneration" and "descending colon inflammation" (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25).…”