Reference

eLife 2020 Oct 16;9:e57920. doi: 10.7554/eLife.57920
57920 cover elife

Authors

Laura Alonso-Herranz, Álvaro Sahún-Español, Ana Paredes, Pilar Gonzalo,Polyxeni Gkontra, Vanessa Núñez, Cristina Clemente, Marta Cedenilla, Maria Villalba-Orero, Javier Inserte, David García-Dorado, Alicia G. Arroyo y Mercedes Ricote.

Abstract

Macrophages (Mφs) produce factors that participate in cardiac repair and remodeling after myocardial infarction (MI); however, how these factors crosstalk with other cell types mediating repair is not fully understood. Here we demonstrated that cardiac Mφs increased the expression of Mmp14 (MT1-MMP) 7 days post-MI. We selectively inactivated the Mmp14 gene in Mφs using a genetic strategy (Mmp14f/f:Lyz2-Cre). This conditional KO (MAC-Mmp14 KO) resulted in attenuated post-MI cardiac dysfunction, reduced fibrosis, and preserved cardiac capillary network. Mechanistically, we showed that MT1-MMP activates latent TGFβ1 in Mφs, leading to paracrine SMAD2-mediated signaling in endothelial cells (ECs) and endothelial-to-mesenchymal transition (EndMT). Post-MI MAC-Mmp14 KO hearts contained fewer cells undergoing EndMT than their wild-type counterparts, and Mmp14-deficient Mφs showed a reduced ability to induce EndMT in co-cultures with ECs. Our results indicate the contribution of EndMT to cardiac fibrosis and adverse remodeling post-MI and identify Mφ MT1-MMP as a key regulator of this process.

Description

El estudio ha descrito un nuevo mecanismo por el que los macrófagos promueven la transición endotelio-mesénquima tras el infarto de miocardio, contribuyendo así a la fibrosis y disfunción cardiacas. Hemos identificado que la metaloproteinasa MT1-MMP es la responsable de este proceso al liberar TGFb de su complejo latente en macrófagos y permitiendo la señalización paracrina en células endoteliales que se transdiferencian amiofibroblastos. Este descubrimiento abre la puerta a la investigación y desarrollo de nuevas terapias para pacientes con infarto de miocardio basadas en modular la actividad de MT1-MMP en los macrófagos. 

Foto equipo subproyecto CNIC

REFERENCIA DEL GRUPO INVESTIGADOR

Los grupos dirigidos por la Dra. Mercedes Ricote (CNIC) y la Dra. Alicia G. Arroyo (CIB.CSIC) estudian la función y regulación transcripcional o por metaloproteasas de los macrófagos y/o células endoteliales en homeostasis y en enfermedades inflamatorias. En este trabajo han combinado sus intereses para analizar la contribución de los macrófagos a la reparación cardiaca que tiene lugar en respuesta al infarto de miocardio, con el objetivo de utilizarlos como dianas terapéuticas en el tratamiento de enfermedades cardiovasculares.

https://www.cnic.es/es/investigacion/senalizacion-receptores-nucleares
https://www.cib.csic.es/es/departamentos/biomedicina-molecular/metaloproteinasas-de-matriz-en-angiogenesis-e-inflamacion

 

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