Novel mechanisms underlying macrophage contribution to cardiac injury after myocardial infarction

Myocardial infarction (MI) is a recognized inflammatory condition that triggers monocyte infiltration and subsequent macrophage differentiation aiming to heal the damage. In the last few years, a growing body of evidence that a timely macrophage expansion and transition from inflammatory to reparati...

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Detalles Bibliográficos
Autor: Alonso-Herranz, Laura
Tipo de recurso: tesis doctoral
Fecha de publicación:2019
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/9031
Acceso en línea:http://hdl.handle.net/20.500.12105/9031
Access Level:acceso abierto
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spelling Novel mechanisms underlying macrophage contribution to cardiac injury after myocardial infarctionAlonso-Herranz, LauraMyocardial infarction (MI) is a recognized inflammatory condition that triggers monocyte infiltration and subsequent macrophage differentiation aiming to heal the damage. In the last few years, a growing body of evidence that a timely macrophage expansion and transition from inflammatory to reparative phenotype are crucial for proper infarct healing has led to macrophages being proposed as potential therapeutic targets for MI. However, cellular and molecular mechanisms involved in these processes remain not well defined. In this study, we aimed to identify novel mechanisms underlying macrophage contribution to cardiac repair, paying special attention to the crosstalk with other cell types. For that purpose, we studied cardiac healing response in adult mice using two models of sterile tissue injury: cryoinjury and permanent occlusion of the left anterior descendant coronary artery (LADligation), employing a combination of state-of-the-art confocal microscopy techniques and algorithms for automatized image analysis, classical cell biology techniques, flow cytometry, and luciferase report assays. We found that infarcts produced by LAD-ligation largely affected myocardium integrity and left ventricular function and remodeling. In contrast, cryoinjury led to mild cardiac dysfunction and remodeling, although it triggered a boosted inflammatory response. Interestingly, elevated levels of the protease MT1-MMP (Mmp14) were detected in post-injury macrophages found in LAD-ligation versus cryoinjury. Based on these observations, we hypothesized that macrophage-derived MT1-MMP may play a role in post-MI adverse cardiac remodeling and dysfunction. Our study demonstrated that MT1-MMP deletion from macrophages (MT1-MMP∆LysM mice) attenuates post-MI cardiac dysfunction, reduces cardiac collagen content and fibrosis, and preserves the cardiac capillary network, improving tissue oxygenation. Mechanistically, we showed that MT1-MMP activates latent TGFβ1 in macrophages, leading to paracrine SMAD2mediated signaling in endothelial cells (ECs), myofibroblasts, and vascular smooth muscle cells. Post-MI hearts from MT1-MMP∆LysM mice contained fewer cells transitioning from an endothelial to a mesenchymal phenotype than their wild-type counterparts, and MT1-MMP-deficient macrophages showed a reduced ability to induce endothelial to mesenchymal transition (EndMT) in co-cultures with ECs. Collectively, this is the first study to demonstrate that post-MI macrophages induce EndMT contributing to adverse cardiac remodeling and to identify MT1-MMP as a key regulator of this process via macrophage-EC crosstalk. This novel mechanism of macrophagemediated EC regulation in the post-MI heart has potential as a therapeutic target in ischemic heart disease.Ricote, Mercedes20202020-02-0520192019-11-2920192019-11-29doctoral thesishttp://purl.org/coar/resource_type/c_db06info:eu-repo/semantics/doctoralThesisapplication/pdfhttp://hdl.handle.net/20.500.12105/9031reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Atribución-NoComercial-CompartirIgual 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-sa/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/90312026-06-12T12:43:37Z
dc.title.none.fl_str_mv Novel mechanisms underlying macrophage contribution to cardiac injury after myocardial infarction
title Novel mechanisms underlying macrophage contribution to cardiac injury after myocardial infarction
spellingShingle Novel mechanisms underlying macrophage contribution to cardiac injury after myocardial infarction
Alonso-Herranz, Laura
title_short Novel mechanisms underlying macrophage contribution to cardiac injury after myocardial infarction
title_full Novel mechanisms underlying macrophage contribution to cardiac injury after myocardial infarction
title_fullStr Novel mechanisms underlying macrophage contribution to cardiac injury after myocardial infarction
title_full_unstemmed Novel mechanisms underlying macrophage contribution to cardiac injury after myocardial infarction
title_sort Novel mechanisms underlying macrophage contribution to cardiac injury after myocardial infarction
dc.creator.none.fl_str_mv Alonso-Herranz, Laura
author Alonso-Herranz, Laura
author_facet Alonso-Herranz, Laura
author_role author
dc.contributor.none.fl_str_mv Ricote, Mercedes
description Myocardial infarction (MI) is a recognized inflammatory condition that triggers monocyte infiltration and subsequent macrophage differentiation aiming to heal the damage. In the last few years, a growing body of evidence that a timely macrophage expansion and transition from inflammatory to reparative phenotype are crucial for proper infarct healing has led to macrophages being proposed as potential therapeutic targets for MI. However, cellular and molecular mechanisms involved in these processes remain not well defined. In this study, we aimed to identify novel mechanisms underlying macrophage contribution to cardiac repair, paying special attention to the crosstalk with other cell types. For that purpose, we studied cardiac healing response in adult mice using two models of sterile tissue injury: cryoinjury and permanent occlusion of the left anterior descendant coronary artery (LADligation), employing a combination of state-of-the-art confocal microscopy techniques and algorithms for automatized image analysis, classical cell biology techniques, flow cytometry, and luciferase report assays. We found that infarcts produced by LAD-ligation largely affected myocardium integrity and left ventricular function and remodeling. In contrast, cryoinjury led to mild cardiac dysfunction and remodeling, although it triggered a boosted inflammatory response. Interestingly, elevated levels of the protease MT1-MMP (Mmp14) were detected in post-injury macrophages found in LAD-ligation versus cryoinjury. Based on these observations, we hypothesized that macrophage-derived MT1-MMP may play a role in post-MI adverse cardiac remodeling and dysfunction. Our study demonstrated that MT1-MMP deletion from macrophages (MT1-MMP∆LysM mice) attenuates post-MI cardiac dysfunction, reduces cardiac collagen content and fibrosis, and preserves the cardiac capillary network, improving tissue oxygenation. Mechanistically, we showed that MT1-MMP activates latent TGFβ1 in macrophages, leading to paracrine SMAD2mediated signaling in endothelial cells (ECs), myofibroblasts, and vascular smooth muscle cells. Post-MI hearts from MT1-MMP∆LysM mice contained fewer cells transitioning from an endothelial to a mesenchymal phenotype than their wild-type counterparts, and MT1-MMP-deficient macrophages showed a reduced ability to induce endothelial to mesenchymal transition (EndMT) in co-cultures with ECs. Collectively, this is the first study to demonstrate that post-MI macrophages induce EndMT contributing to adverse cardiac remodeling and to identify MT1-MMP as a key regulator of this process via macrophage-EC crosstalk. This novel mechanism of macrophagemediated EC regulation in the post-MI heart has potential as a therapeutic target in ischemic heart disease.
publishDate 2019
dc.date.none.fl_str_mv 2019
2019-11-29
2019
2019-11-29
2020
2020-02-05
dc.type.none.fl_str_mv doctoral thesis
http://purl.org/coar/resource_type/c_db06
dc.type.openaire.fl_str_mv info:eu-repo/semantics/doctoralThesis
format doctoralThesis
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12105/9031
url http://hdl.handle.net/20.500.12105/9031
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución-NoComercial-CompartirIgual 4.0 Internacional
http://creativecommons.org/licenses/by-nc-sa/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
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Atribución-NoComercial-CompartirIgual 4.0 Internacional
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eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
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