Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ1 after myocardial infarction.

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)...

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Bibliographic Details
Authors: Alonso-Herranz, Laura, Sahun-Español, Alvaro, Paredes, Ana, Gonzalo, Pilar, Gkontra, Polyxeni, Nunez, Vanessa, Clemente, Cristina, Cedenilla, Marta, Villalba-Orero, Maria, Inserte, Javier, Garcia-Dorado, David, Arroyo, Alicia G, Ricote, Mercedes
Format: article
Publication Date:2020
Country:España
Institution:Instituto de Salud Carlos III (ISCIII)
Repository:Repisalud
Language:English
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/13182
Online Access:http://hdl.handle.net/20.500.12105/13182
Access Level:Open access
Keyword:Epithelial-Mesenchymal Transition
Animals
Collagen
Disease Models, Animal
Endothelium, Vascular
Female
Fibrosis
Flow Cytometry
Gene Expression Regulation
HEK293 Cells
Humans
Macrophages
Male
Matrix Metalloproteinase 14
Mice
Mice, Inbred C57BL
Mice, Knockout
Microcirculation
Myocardial Infarction
Phenotype
Reperfusion Injury
Transforming Growth Factor beta1
Ventricular Dysfunction, Left
Description
Summary: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.

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