Novel mechanisms underlying macrophage contribution to cardiac injury after myocardial infarction

• Autores: Laura Alonso Herranz
• Directores de la Tesis: Mercedes Ricote Pacheco (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2019
• Idioma: español
• Tribunal Calificador de la Tesis: Enrique Lara Pezzi (presid.), Ángel Luis Corbi Lopez (secret.), Raffaele Strippoli (voc.)
• Programa de doctorado: Programa de Doctorado en Biociencias Moleculares por la Universidad Autónoma de Madrid
• Materias:
  • Ciencias de la vida
    • Inmunología
    • Biología molecular
  • Ciencias médicas
    • Medicina interna
      • Cardiología
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • 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 (LAD-ligation), employing a combination of state-of-the-art confocal microscopy techniques and algorithms for automatized image analysis, classical cell biology techniques, flow cytometry, and highly sensitive 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 SMAD2-mediated 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 macrophage-mediated EC regulation in the post-MI heart has potential as a therapeutic target in ischemic heart disease.