Targeting cardiomyocyte ADAM10 ectodomain shedding promotes survival early after myocardial infarction

Erik Klapproth, Anke Witt, Pauline Klose, Johanna Wiedemann, Nikitha Vavilthota, Stephan R. Künzel, Susanne Kämmerer, Mario Günscht, David Sprott, Mathias Lesche, Fabian Rost, Andreas Dahl, Erik Rauch, Lars Kattner, Silvio Weber, Peter Mirtschink, Irakli Kopaliani, Kaomei Guan, Kristina Lorenz, Paul Saftig, Michael Wagner and Ali El-Armouche ()
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Erik Klapproth: Technische Universität Dresden
Anke Witt: Technische Universität Dresden
Pauline Klose: Technische Universität Dresden
Johanna Wiedemann: Technische Universität Dresden
Nikitha Vavilthota: Technische Universität Dresden
Stephan R. Künzel: Technische Universität Dresden
Susanne Kämmerer: Technische Universität Dresden
Mario Günscht: Technische Universität Dresden
David Sprott: Technische Universität Dresden
Mathias Lesche: Technische Universität Dresden
Fabian Rost: Technische Universität Dresden
Andreas Dahl: Technische Universität Dresden
Erik Rauch: Endotherm GmbH
Lars Kattner: Endotherm GmbH
Silvio Weber: Technische Universität Dresden
Peter Mirtschink: Technische Universität Dresden
Irakli Kopaliani: Technische Universität Dresden
Kaomei Guan: Technische Universität Dresden
Kristina Lorenz: Julius-Maximilians-University of Würzburg
Paul Saftig: Biochemical Institute, Christian-Albrechts-Universität Kiel
Michael Wagner: Technische Universität Dresden
Ali El-Armouche: Technische Universität Dresden

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract After myocardial infarction the innate immune response is pivotal in clearing of tissue debris as well as scar formation, but exaggerated cytokine and chemokine secretion with subsequent leukocyte infiltration also leads to further tissue damage. Here, we address the value of targeting a previously unknown a disintegrin and metalloprotease 10 (ADAM10)/CX3CL1 axis in the regulation of neutrophil recruitment early after MI. We show that myocardial ADAM10 is distinctly upregulated in myocardial biopsies from patients with ischemia-driven cardiomyopathy. Intriguingly, upon MI in mice, pharmacological ADAM10 inhibition as well as genetic cardiomycyte-specific ADAM10 deletion improves survival with markedly enhanced heart function and reduced scar size. Mechanistically, abolished ADAM10-mediated CX3CL1 ectodomain shedding leads to diminished IL-1β-dependent inflammation, reduced neutrophil bone marrow egress as well as myocardial tissue infiltration. Thus, our data shows a conceptual insight into how acute MI induces chemotactic signaling via ectodomain shedding in cardiomyocytes.

Date: 2022
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DOI: 10.1038/s41467-022-35331-0

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