Targeting myeloid cell coagulation signaling blocks MAP kinase/TGF-β1-driven fibrotic remodeling in ischemic heart failure.

Autor:	Garlapati V; Center for Thrombosis and Hemostasis and.; Department of Cardiology, University Medical Center Mainz, Mainz, Germany.; German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany., Molitor M; Center for Thrombosis and Hemostasis and.; Department of Cardiology, University Medical Center Mainz, Mainz, Germany.; German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany., Michna T; Institute of Immunology, University Medical Center Mainz, Mainz, Germany., Harms GS; Cell Biology Unit, University Medical Center Mainz, Mainz, Germany and.; Departments of Biology and Physics, Wilkes University, Wilkes-Barre, Pennsylvania, USA., Finger S; Center for Thrombosis and Hemostasis and.; Department of Cardiology, University Medical Center Mainz, Mainz, Germany., Jung R; Center for Thrombosis and Hemostasis and.; Department of Cardiology, University Medical Center Mainz, Mainz, Germany.; Institute for Molecular Medicine, University Medical Center Mainz, Mainz, Germany., Lagrange J; Center for Thrombosis and Hemostasis and., Efentakis P; Center for Thrombosis and Hemostasis and., Wild J; Center for Thrombosis and Hemostasis and.; Department of Cardiology, University Medical Center Mainz, Mainz, Germany.; German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany., Knorr M; Center for Thrombosis and Hemostasis and.; Department of Cardiology, University Medical Center Mainz, Mainz, Germany., Karbach S; Center for Thrombosis and Hemostasis and.; Department of Cardiology, University Medical Center Mainz, Mainz, Germany.; German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany., Wild S; Center for Thrombosis and Hemostasis and.; Department of Cardiology, University Medical Center Mainz, Mainz, Germany.; German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany., Vujacic-Mirski K; Department of Cardiology, University Medical Center Mainz, Mainz, Germany., Münzel T; Center for Thrombosis and Hemostasis and.; Department of Cardiology, University Medical Center Mainz, Mainz, Germany.; German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany., Daiber A; Department of Cardiology, University Medical Center Mainz, Mainz, Germany.; German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany., Brandt M; Center for Thrombosis and Hemostasis and.; Department of Cardiology, University Medical Center Mainz, Mainz, Germany.; German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany., Gori T; Department of Cardiology, University Medical Center Mainz, Mainz, Germany.; German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany., Milting H; Erich und Hanna Klessmann-Institut für Kardiovaskuläre Forschung und Entwicklung, Herz- und Diabeteszentrum NRW, Bad Oeynhausen, Germany., Tenzer S; Institute of Immunology, University Medical Center Mainz, Mainz, Germany.; Helmholtz Institute for Translational Oncology (HI-TRON) Mainz, Germany and.; German Cancer Research Center (DKFZ), Heidelberg, Germany., Ruf W; Center for Thrombosis and Hemostasis and.; German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany.; Department of Immunology and Microbiology, Scripps Research, La Jolla, California, USA., Wenzel P; Center for Thrombosis and Hemostasis and.; Department of Cardiology, University Medical Center Mainz, Mainz, Germany.; German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2023 Feb 15; Vol. 133 (4). Date of Electronic Publication: 2023 Feb 15.
DOI:	10.1172/JCI156436
Abstrakt:	Despite major advances in acute interventions for myocardial infarction (MI), adverse cardiac remodeling and excess fibrosis after MI causing ischemic heart failure (IHF) remain a leading cause of death worldwide. Here we identify a profibrotic coagulation signaling pathway that can be targeted for improved cardiac function following MI with persistent ischemia. Quantitative phosphoproteomics of cardiac tissue revealed an upregulated mitogen-activated protein kinase (MAPK) pathway in human IHF. Intervention in this pathway with trametinib improves myocardial function and prevents fibrotic remodeling in a murine model of non-reperfused MI. MAPK activation in MI requires myeloid cell signaling of protease-activated receptor 2 linked to the cytoplasmic domain of the coagulation initiator tissue factor (TF). They act upstream of pro-oxidant NOX2 NADPH oxidase, ERK1/2 phosphorylation, and activation of profibrotic TGF-β1. Specific targeting with the TF inhibitor nematode anticoagulant protein c2 (NAPc2) starting 1 day after established experimental MI averts IHF. Increased TF cytoplasmic domain phosphorylation in circulating monocytes from patients with subacute MI identifies a potential thromboinflammatory biomarker reflective of increased risk for IHF and suitable for patient selection to receive targeted TF inhibition therapy.
Databáze:	MEDLINE
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