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Egorov, D.* ; Kopaliani, I.* ; Ameln, A.K.* ; Speier, S. ; Deussen, A.*

Mechanism of pro-MMP9 activation in co-culture of pro-inflammatory macrophages and cardiomyocytes.

Exp. Cell Res. 434, 113868 (2023)

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OBJECTIVE: A wide range of cardiac diseases is associated with inflammation. "Inflamed" heart tissue is infiltrated with pro-inflammatory macrophages which extensively secrete matrix metalloproteinase 9 (MMP9), a regulator of extracellular matrix turnover. As MMP9 is released from macrophages in a latent form, it requires activation. The present study addresses the role of cardiomyocytes in the course of this activation process. METHODS AND RESULTS: In mono- and co-cultures of pro-inflammatory rat macrophages (bone marrow-derived and peritoneal) and cardiomyocytes (H9C2 cell line) gelatin zymography demonstrated that activated macrophages robustly secreted latent pro-MMP9, whereas cardiomyocytes could not produce the enzyme. Co-culturing of the two cell species was critical for pro-MMP9 activation and was also accompanied by processing of cardiomyocyte-secreted pro-MMP2. A cascade of pro-MMP9 activation was initiated on macrophage membrane with pro-MMP2 cleavage. Namely, pro-inflammatory macrophages expressed an active membrane type 1 MMP (MT1MMP), which activated pro-MMP2, which in turn converted pro-MMP9. Downregulation of MT1MMP in macrophages by siRNA abolished activation of both pro-MMP2 and pro-MMP9 in co-culture. In addition, both cell species secreted MMP13 as a further pro-MMP9 activator. In co-culture, activation of pro-MMP13 occurred on membranes of macrophages and was enhanced in presence of active MMP2. Using incubations with recombinant MMPs and isolated macrophage membranes, we demonstrated that while both MMP2 and MMP13 individually had the ability to activate pro-MMP9, their combined action provided a synergistic effect. CONCLUSION: Activation of pro-MMP9 in a co-culture of pro-inflammatory macrophages and cardiomyocytes was the result of a complex interaction of several MMPs on the cell membrane and in the extracellular space. Both cell types contributed critically to pro-MMP9 processing.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Cardiac Remodeling ; Cardiovascular Disease ; Extracellular Proteases ; Wound Healing; Heart-failure Rats; Matrix Metalloproteinases; Extracellular-matrix; Myocardial-infarction; Matrix-metalloproteinase-9; Expression; Mmp; Deletion; Timp-2; Form

ISSN (print) / ISBN 1090-2422

e-ISSN 0014-4827

Journal Experimental Cell Research

Quellenangaben Volume: 434, Issue: 1, Pages: 113868

Publisher Academic Press

Publishing Place Orlando, Fla.

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute for Pancreatic Beta Cell Research (IPI)

Grants Faculty of Medicine at Technische Universitat Dresden