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

J Clin Invest. 2023 Feb 15;133(4):e156436. doi: 10.1172/JCI156436.


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.

Keywords: Cardiovascular disease; Coagulation; Heart failure; Immunology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Fibrosis
  • Heart Failure* / metabolism
  • Heart Failure* / pathology
  • Humans
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism
  • Myeloid Cells* / metabolism
  • Myocardial Infarction* / metabolism
  • Signal Transduction
  • Transforming Growth Factor beta1 / metabolism
  • Ventricular Remodeling


  • Mitogen-Activated Protein Kinases
  • Transforming Growth Factor beta1
  • anti-coagulant protein C2, Ancylostoma caninum