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El receptor tipo peaje 3 media la estenosis aórtica a través de un mecanismo conservado de calcificación

Can Gollmann-Tepeköylü¹, Michael Graber¹, Jakob Hirsch¹

¹Department of Cardiac Surgery (C.G.-T., M.G, J.H., S.M., L.P., F.N., E.K., N.F., D. Lobenwein, V.S., J.E., M.G., J.H.), Medical University of Innsbruck, Austria.

|April 4, 2023

Resumen

El receptor tipo peaje 3 (TLR3) regula la calcificación en las válvulas aórticas. Biglycan (BGN) activa el TLR3, promoviendo la formación ósea en las células valvulares y contribuyendo a la enfermedad de la válvula aórtica calcificada (CAVD).

Área de la Ciencia:

Biología molecular e inmunología
Investigación cardiovascular
Biología esquelética

Sus antecedentes:

La enfermedad de la válvula aórtica calcifica (CAVD) implica que las células intersticiales valvulares se transforman en células formadoras de hueso.
Los receptores de tipo Toll (TLR) son clave en la inmunidad innata y la reparación de tejidos.
Los interferones de tipo I (IFN) son vitales para las respuestas antivirales y la formación ósea.

Objetivo del estudio:

Investigar si los ligandos endógenos TLR3 en las válvulas aórticas promueven la generación de células similares a los osteoblastos a través de la señalización IFN de tipo I.
Identificar los mecanismos moleculares que vinculan la TLR3, las IFN y la patogénesis de la CAVD.

Principales métodos:

Las células intersticiales valvulares humanas fueron estimuladas con tensión mecánica o agonistas TLR3.
Se analizaron la expresión génica, la señalización IFN y la formación ósea; los inhibidores delinearon las vías.
En el modelado silico y la inmunoprecipitación se verificaron las interacciones ligando-receptor; se utilizaron modelos de ratones knockout y peces cebra; se analizaron cohortes humanas (GERA, UK Biobank) en busca de asociaciones genéticas.

Principales resultados:

TLR3 fue identificado como un regulador clave de la calcificación valvular.
Se descubrió que el biglicano (BGN) es un agonista endógeno de TLR3, que requiere maduración posttranslacional por la xilosiltransferasa 1 (XYLT1) para su activación.
BGN indujo la transdiferenciación de células intersticiales valvulares en osteoblastos a través de la señalización IFN de tipo I dependiente de TLR3; los ratones con deficiencia de BGN, Tlr3 e Ifnar1 mostraron protección contra la CAVD y la formación ósea deteriorada. Las variaciones genéticas en la vía XYLT1-BGN-TLR3-IFNAR1 se asociaron con CAVD en cohortes humanas.

Conclusiones:

El eje Biglycan (BGN) -TLR3-IFNAR1 es una vía evolutivamente conservada que regula la calcificación de la válvula aórtica.
Esta vía representa un objetivo terapéutico potencial para la prevención de la EACV.

Palabras clave:

Receptor tipo peaje 3 Enfermedad de la válvula aórtica el biglicano Matriz extracelular Osteogénesis Proteínas

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