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p38 La proteína quinasa activada por mitógeno desactiva las células progenitoras endoteliales

Florian H Seeger¹, Judith Haendeler, Dirk H Walter

¹Molecular Cardiology, Department of Internal Medicine III, University of Frankfurt, Theodor-Stern-Kai 7, Frankfurt, Germany.

|March 9, 2005

Resumen

p38 La activación de la MAP quinasa por la glucosa y el TNF-alfa reduce el número de células progenitoras endoteliales (EPC). La inhibición de la quinasa p38 con SB203580 aumenta las EPC y mejora la neovascularización, ofreciendo potencial para la terapia celular.

Área de la Ciencia:

Biología Cardiovascular Biología Cardiovascular
La señalización celular de las células.
La Medicina Regenerativa es una Medicina Regenerativa.

Sus antecedentes:

Las células progenitoras endoteliales (EPC) son cruciales para la neovascularización, pero se reducen y se ven afectadas funcionalmente en pacientes con enfermedad arterial coronaria (CAD) o diabetes.
Investigar el impacto de factores de riesgo como la glucosa y el TNF-alfa en las EPC es vital para comprender estos trastornos.

Objetivo del estudio:

Aclarar los mecanismos por los cuales la glucosa y el TNF-alfa afectan el número y la función de EPC.
Determinar el papel de la señalización de la quinasa p38 MAP en la regulación de las EPC.

Principales métodos:

EPCs aislados de sujetos sanos y pacientes con CAD.
EPCs tratados con diferentes concentraciones de glucosa y TNF-alfa.
Se analizó la activación de la vía de la quinasa p38 MAP (fosforilación de p38, MSK1, CREB).
Utilizó un inhibidor de la quinasa p38 (SB203580) y el adenovirus p38 dominante negativo.
Se evaluó el número de EPC, la apoptosis, la proliferación, los marcadores de diferenciación (CD14, CD64) y la capacidad de neovascularización in vivo.

Principales resultados:

La glucosa y el TNF-alfa, dependiendo de la dosis, redujeron los números de EPC sin inducir apoptosis.
Ambos factores activaron la vía de la quinasa p38 MAP, incluidas las quinasas aguas abajo y los factores de transcripción.
Los pacientes con CAD exhibieron una mayor fosforilación basal de p38.
La inhibición de la quinasa p38 aumentó significativamente el número de EPC y la proliferación.
El tratamiento SB203580 restauró parcialmente la capacidad de neovascularización en EPCs derivadas de pacientes con CAD in vivo.
El aumento de EPCs se correlacionó con la expresión reducida de marcadores monocíticos, lo que sugiere una diferenciación alterada.

Conclusiones:

p38 La MAP quinasa es un regulador clave del número y la función de las EPC.
La inhibición de la quinasa p38 puede contrarrestar los efectos perjudiciales de la glucosa y el TNF-alfa en las EPC.
SB203580 tiene potencial para mejorar los números de EPC para terapias basadas en células en enfermedades cardiovasculares.

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