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

Alvaro Becerra, MacArena Rojas, Alejandro Vallejos, Vicente Villegas, Lorena Pérez, Claudio Cabello-Verrugio, Felipe Simon

Resultado de la investigación: Research - revisión exhaustivaArticle

Resumen

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.

IdiomaEnglish
Páginas1033-1046
Número de páginas14
PublicaciónLaboratory Investigation
Volumen97
Número de edición9
DOI
EstadoPublished - 1 sep 2017
Publicado de forma externa

Huella dactilar

STAT3 Transcription Factor
Transforming Growth Factors
Fibrosis
TGF-beta type I receptor
Endothelial Cells
Proteins
Extracellular Matrix Proteins
Fibroblasts
Smad Proteins
Inflammation Mediators
Transforming Growth Factor beta
Blood Vessels
Down-Regulation
Pathology
Genes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

Citar esto

Becerra, Alvaro ; Rojas, MacArena ; Vallejos, Alejandro ; Villegas, Vicente ; Pérez, Lorena ; Cabello-Verrugio, Claudio ; Simon, Felipe. / Endothelial fibrosis induced by suppressed STAT3 expression mediated by signaling involving the TGF-β1/ALK5/Smad pathway. En: Laboratory Investigation. 2017 ; Vol. 97, N.º 9. pp. 1033-1046
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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.",
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Endothelial fibrosis induced by suppressed STAT3 expression mediated by signaling involving the TGF-β1/ALK5/Smad pathway. / Becerra, Alvaro; Rojas, MacArena; Vallejos, Alejandro; Villegas, Vicente; Pérez, Lorena; Cabello-Verrugio, Claudio; Simon, Felipe.

En: Laboratory Investigation, Vol. 97, N.º 9, 01.09.2017, p. 1033-1046.

Resultado de la investigación: Research - revisión exhaustivaArticle

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