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

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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.
Funding Information
  • BMBF (01EO1003, 01EO1503)
  • German Research Foundation (371/47-1 FUGG, WE4361/7-1, KA-4035/1-1)
  • German Center for Cardiovascular Research (N/A)
  • Boehringer-Ingelheim-Foundation (N/A)
  • Alexander-von-Humboldt foundation (AvH Ruf)
  • Else-Kröner-Fresenius-Foundation (N/A)

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