Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFß1 after myocardial infarction.
Elife
; 92020 10 16.
Article
in En
| MEDLINE
| ID: mdl-33063665
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/fLyz2-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 TGFß1 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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Endothelium, Vascular
/
Matrix Metalloproteinase 14
/
Transforming Growth Factor beta1
/
Epithelial-Mesenchymal Transition
/
Macrophages
/
Myocardial Infarction
Type of study:
Prognostic_studies
Limits:
Animals
/
Female
/
Humans
/
Male
Language:
En
Journal:
Elife
Year:
2020
Document type:
Article
Affiliation country:
Spain