Targeting myeloid cell coagulation signaling blocks MAP kinase/TGF-β1–driven fibrotic remodeling in ischemic heart failure
Venkata Garlapati, … , Wolfram Ruf, Philip Wenzel
Venkata Garlapati, … , Wolfram Ruf, Philip Wenzel
Published December 22, 2022
Citation Information: J Clin Invest. 2023;133(4):e156436. https://doi.org/10.1172/JCI156436.
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Research Article Immunology

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

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 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.

Authors

Venkata Garlapati, Michael Molitor, Thomas Michna, Gregory S. Harms, Stefanie Finger, Rebecca Jung, Jeremy Lagrange, Panagiotis Efentakis, Johannes Wild, Maike Knorr, Susanne Karbach, Sabine Wild, Ksenija Vujacic-Mirski, Thomas Münzel, Andreas Daiber, Moritz Brandt, Tommaso Gori, Hendrik Milting, Stefan Tenzer, Wolfram Ruf, Philip Wenzel

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Figure 3

Infiltrating myeloid cells are the major source for increased MAPK1 activation in a preclinical model of non-reperfused MI.

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Infiltrating myeloid cells are the major source for increased MAPK1 acti...
Confocal microscopy of whole LV myocardial cryosections obtained from n = 3–5 C57BL/6J mice after 7 days of permanent LAD ligation. (A) Representative images of p-ERK1/2+ cells costained for CD31, CD45, α-SMA, cTNT. Scale bars: 500 μm. (B) Top: Quantification of p-ERK1/2+ intensity in remote, border, and infarction regions at days 1, 3, and 7 after MI. Bottom: Quantification of colocalization analysis of p-ERK1/2 signal intensity with CD31, CD45, α-SMA, and cTNT in border and infarct regions at day 7 after MI using Pearson’s correlation coefficient. RAU, relative arbitrary units. (C) Experimental design: C57BL/6J mice were subjected to permanent LAD ligation versus sham surgery and given trametinib (1 mg/kg/d) or vehicle treatment once daily via oral gavage from day 1 to day 7. (D) High-frequency ultrasound echocardiography obtained in parasternal long axis with measurement of LV ejection fraction (LVEF, %) and LV end-diastolic volume (LVEDV, μL) on day 7 after operation. Ordinary 1-way ANOVA, Šidák’s multiple-comparison test; n = 4–6 animals per group. Data are shown as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.