학술논문
Targeting myeloid cell coagulation signaling blocks MAP kinase/TGF-β1-driven fibrotic remodeling in ischemic heart failure.
Document Type
Article
Author
Garlapati, Venkata; Molitor, Michael; Michna, Thomas; Harms, Gregory S.; Finger, Stefanie; Jung, Rebecca; Lagrange, Jeremy; Efentakis, Panagiotis; Wild, Johannes; Knorr, Maike; Karbach, Susanne; Wild, Sabine; Vujacic-Mirski, Ksenija; Münzel, Thomas; Daiber, Andreas; Brandt, Moritz; Gori, Tommaso; Milting, Hendrik; Tenzer, Stefan; Ruf, Wolfram
Source
Subject
*MYELOID cells
*CELL communication
*HEART failure
*MYOCARDIAL infarction
*NADPH oxidase
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Language
ISSN
0021-9738
Abstract
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 proteaseactivated 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-ß1. 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. [ABSTRACT FROM AUTHOR]