Participación de STAT3 en la fibrosis de células endoteliales vasculares
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Fecha
2016
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Facultad/escuela
Idioma
es
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Universidad Andrés Bello
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Licencia CC
Licencia CC
Resumen
Un evento importante para el desarrollo de enfermedades cardiovasculares corresponde a la disfunción endotelial. Entre otras características, este evento comprende la transformación fibrótica del endotelio mediante un proceso denominado fibrosis endotelial. Durante este proceso, las células endoteliales cambian tanto su morfología como su patrón de expresión de proteínas a través de un mecanismo denominado transición endotelio-mesénquima. La fibrosis endotelial está caracterizada por la disminución de proteínas endoteliales (VE-CAD y CD-31), el aumento de proteínas fibróticas (FSP-1 y -SMA) y un incremento de componentes de la matriz extracelular (FN y Col III). Un inductor muy estudiado de fibrosis es el TGFβ-1, citoquina que estimula la producción de componentes fibróticos, contribuyendo a la generación de fibrosis. Por otro lado, existe evidencia que apunta a la participación del factor transcripcional STAT3 en el proceso de fibrosis celular. Nosotros observamos en nuestro laboratorio que la disminución de la expresión de STAT3 en células endoteliales produce un fenotipo tipo fibroblasto. Adicionalmente, observamos que la disminución de la expresión de STAT3 genera la síntesis y secreción de TGFβ-1, sugiriendo que esta citoquina y su vía de señalización intracelular podrían estar implicadas en el desarrollo de este fenotipo fibrótico.
Así, nuestra hipótesis de trabajo es que la inhibición de la expresión de STAT3 induce fibrosis endotelial a través de un mecanismo mediado por la vía de señalización de TGFβ-1. En consecuencia, el objetivo general de este trabajo es evaluar si la inhibición de la expresión de STAT3 induce la fibrosis endotelial a través de un mecanismo mediado por la vía de señalización de TGFβ-1. Utilizando cultivos primarios de células endoteliales de mesenterio de rata y la transfección de un siRNA contra STAT3, concluimos que: 1) La inhibición de la expresión de STAT3 produce un cambio fenotípico tipo fibroblasto; 2) La inhibición de la expresión de STAT3 produce disminución de la expresión de marcadores endoteliales (VE-CAD y CD-31), además de un aumento de la expresión de marcadores fibróticos (FSP-1 y α-SMA) y de proteínas de la MEC (FN y Col III) así como la translocación de Smad4 desde el citoplasma al núcleo; 3) La inhibición del receptor de TGFβ-1, ALK-5, previene los efectos fibróticos producidos por la inhibición de la expresión de STAT3.
Endothelial dysfunction is an important event necessary for cardiovascular diseases development. Among other features, this event comprises the endothelium fibrotic transformation through a process known as endothelial fibrosis. During this process, endothelial cells change their morphology and its protein expression pattern through a mechanism known as endothelial-to-mesenchymal transition. Endothelial fibrosis is characterized by decreasing endothelial proteins (VE-cad and CD-31), increasing fibrotic protein (FSP-1 and α-SMA) and an increase of components of the extracellular matrix (FN and Col III). A much studied inducer of fibrosis is TGFβ-1, cytokine that stimuli the production of fibrotic compounds, promoting fibrosis. Furthermore, there is evidence pointing to the involvement of the STAT3 transcription factor in cell fibrosis process. We observed in our laboratory that the decreased STAT3 expression in endothelial cells produces a fibroblast-like phenotype. Additionally we detected that decreased STAT3 expression generates the synthesis and secretion of TGFβ-1, suggesting that this cytokine and their intracellular signaling pathway may be involved in the development of this fibrotic phenotype. Thus, our hypothesis is that inhibition of STAT3 expression induces endothelial fibrosis through TGFβ-1 signaling pathway mechanism. Consequently, the overall objective of this work is demonstrate that inhibition of STAT3 expression induces endothelial fibrosis through a TGFβ-1 signaling pathway mechanism. Using primary cultures of rat mesentery endothelial cells and transfection of siRNA against STAT3 to decrease its expression, we conclude that: 1) Inhibition of STAT3 expression produces a fibroblast-like phenotype; 2) Inhibition of STAT3 expression results in decreased expression of endothelial markers (VE-Cad and CD-31), an increase of fibrotic markers expression (FSP-1 and α-SMA) and ECM proteins (FN and Col III) and Smad4 translocation from the cytoplasm to the nucleus; 3) Inhibition of TGFβ-1 receptor, ALK-5, prevent fibrotic effects caused by STAT3 inhibition expression.
Endothelial dysfunction is an important event necessary for cardiovascular diseases development. Among other features, this event comprises the endothelium fibrotic transformation through a process known as endothelial fibrosis. During this process, endothelial cells change their morphology and its protein expression pattern through a mechanism known as endothelial-to-mesenchymal transition. Endothelial fibrosis is characterized by decreasing endothelial proteins (VE-cad and CD-31), increasing fibrotic protein (FSP-1 and α-SMA) and an increase of components of the extracellular matrix (FN and Col III). A much studied inducer of fibrosis is TGFβ-1, cytokine that stimuli the production of fibrotic compounds, promoting fibrosis. Furthermore, there is evidence pointing to the involvement of the STAT3 transcription factor in cell fibrosis process. We observed in our laboratory that the decreased STAT3 expression in endothelial cells produces a fibroblast-like phenotype. Additionally we detected that decreased STAT3 expression generates the synthesis and secretion of TGFβ-1, suggesting that this cytokine and their intracellular signaling pathway may be involved in the development of this fibrotic phenotype. Thus, our hypothesis is that inhibition of STAT3 expression induces endothelial fibrosis through TGFβ-1 signaling pathway mechanism. Consequently, the overall objective of this work is demonstrate that inhibition of STAT3 expression induces endothelial fibrosis through a TGFβ-1 signaling pathway mechanism. Using primary cultures of rat mesentery endothelial cells and transfection of siRNA against STAT3 to decrease its expression, we conclude that: 1) Inhibition of STAT3 expression produces a fibroblast-like phenotype; 2) Inhibition of STAT3 expression results in decreased expression of endothelial markers (VE-Cad and CD-31), an increase of fibrotic markers expression (FSP-1 and α-SMA) and ECM proteins (FN and Col III) and Smad4 translocation from the cytoplasm to the nucleus; 3) Inhibition of TGFβ-1 receptor, ALK-5, prevent fibrotic effects caused by STAT3 inhibition expression.
Notas
Tesis (Magíster en Biotecnología)
Palabras clave
Factor de Transcripción STAT3, Endotelio Vascular