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Updated: Aug 16, 2025
Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes
Published on: June 3, 2018
Targeting myeloid cell coagulation signaling blocks MAP kinase/TGF-β1-driven fibrotic remodeling in ischemic heart
Venkata Garlapati1,2,3, Michael Molitor1,2,3, Thomas Michna4
1Center for Thrombosis and Hemostasis and.
Insights
Targeting a profibrotic pathway involving tissue factor (TF) can improve cardiac function after myocardial infarction (MI). This discovery offers new hope for treating ischemic heart failure (IHF) by preventing cardiac fibrosis.
Area of Science:
- Cardiovascular Biology
- Coagulation and Thrombosis
- Molecular Medicine
Background:
- Myocardial infarction (MI) can lead to ischemic heart failure (IHF) due to adverse cardiac remodeling and fibrosis, a major global health concern.
- Current acute interventions for MI do not fully address post-MI cardiac dysfunction and fibrosis.
Purpose of the Study:
- To identify and characterize a profibrotic coagulation signaling pathway involved in post-MI cardiac remodeling.
- To evaluate therapeutic strategies targeting this pathway for improved cardiac function after MI.
Main Methods:
- Quantitative phosphoproteomics of human cardiac tissue from IHF patients.
- Pharmacological intervention with trametinib (a MAPK inhibitor) in a murine model of non-reperfused MI.
- Investigating the role of myeloid cell signaling, protease-activated receptor 2, and tissue factor (TF) in MAPK activation.
- Assessing the efficacy of TF inhibition using nematode anticoagulant protein c2 (NAPc2).
- Analyzing TF cytoplasmic domain phosphorylation in monocytes from subacute MI patients.
Main Results:
- Upregulation of the mitogen-activated protein kinase (MAPK) pathway was observed in human IHF.
- Trametinib treatment improved myocardial function and prevented fibrotic remodeling in a murine MI model.
- MAPK activation in MI was dependent on myeloid cell signaling via protease-activated receptor 2, linked to TF.
- TF signaling acts upstream of NOX2, ERK1/2 phosphorylation, and TGF-β1 activation.
- NAPc2 treatment initiated post-MI averted IHF in experimental models.
- Elevated TF cytoplasmic domain phosphorylation in monocytes of subacute MI patients may serve as a biomarker for IHF risk.
Conclusions:
- A profibrotic coagulation pathway involving TF and MAPK signaling contributes to adverse cardiac remodeling and IHF post-MI.
- Targeting TF with inhibitors like NAPc2 presents a promising therapeutic strategy for preventing IHF.
- TF cytoplasmic domain phosphorylation in monocytes could identify patients at high risk for IHF, enabling personalized therapeutic approaches.
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.
