Key result
Macrophage-specific MT1-MMP deletion attenuates post-MI cardiac dysfunction and fibrosis by reducing endothelial-to-mesenchymal transition.
Why the study?
Macrophages produce factors that participate in cardiac repair and remodeling after myocardial infarction, but how these factors crosstalk with other cell types mediating repair is not fully understood.
Macrophage MT1-MMP promotes adverse cardiac remodeling and fibrosis post-MI by activating TGFβ1 and inducing endothelial-to-mesenchymal transition, identifying it as a potential therapeutic target.
Macrophage MT1-MMP merits exploration as a post-MI target; hypothesis-generating and requires human validation before any clinical consideration.
Macrophages 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. In this study, we demonstrated that cardiac macrophages increased expression of Mmp14 (MT1-MMP) 7 days post-MI. Specific macrophage-targeting of MT1-MMP (MT1-MMP ΔLysM mice) attenuates post-MI cardiac dysfunction, reduces fibrosis, and preserves the cardiac capillary network. Mechanistically, we showed that MT1-MMP activates latent TGFβ1 in macrophages, leading to paracrine SMAD2-mediated signaling in endothelial cells and endothelial-to-mesenchymal transition (EndMT). Post-MI MT1-MMP ΔLysM hearts contained fewer cells undergoing EndMT than their wild-type counterparts, and MT1-MMP-deficient macrophages showed a reduced ability to induce EndMT in co-cultures with endothelial cells. Our results demonstrate the contribution of EndMT to cardiac fibrosis and adverse remodeling post-MI and identify macrophage MT1-MMP as a key regulator of this process. The identified mechanism has potential as a therapeutic target in ischemic heart disease.
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Alonso-Herranz et al. (2020) studied Myocardial infarction. Macrophage-specific deletion of MT1-MMP (MT1-MMP ΔLysM mice) vs. Wild-type counterparts was evaluated on Cardiac dysfunction, fibrosis, and endothelial-to-mesenchymal transition. Macrophage-specific deletion of MT1-MMP attenuated post-MI cardiac dysfunction, reduced fibrosis, and preserved the capillary network by reducing endothelial-to-mesenchymal transition.
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