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    Oral Communication

    Hemostatic Systems in Cancer, Inflammation and Immunity

    Mechanisms of Cardiovascular and Neurologic Diseases

    OC 49.4 - Targeting myeloid cell coagulation signaling blocks MAP kinase/TGF-β1 driven fibrotic remodeling, improves cardiac function and improves survival in ischemic heart failure

    Monday, June 26, 2023
    15:30 – 15:45 ET
    Room: 515
    Session Available As: On-Demand

      Co-Author(s)

    • VG

      Venkata Garlapati

      Postdoctoral Researcher
      Center for Thrombosis and Hemostasis, University Medical Center Mainz, Germany
      Mainz, Rheinland-Pfalz, Germany

      • Co-Author(s)

    • MM

      Michael Molitor

      Postdoctoral Researcher
      University Medical Center Mainz, Germany
      Mainz, Rheinland-Pfalz, Germany

    • TM

      Thomas Michna

      PhD Student
      University Medical Center Mainz, Germany
      Mainz, Rheinland-Pfalz, Germany

    • SF

      Stefanie Finger

      Postdoctoral Researcher
      University Medical Center Mainz, Germany
      Mainz, Rheinland-Pfalz, Germany

    • GH

      Gergory Harms

      Professor
      University Medical Center Mainz, Germany
      Mainz, Rheinland-Pfalz, Germany

    • AD

      Andreas Daiber

      Professor
      University Medical Center Mainz, Germany
      Mainz, Rheinland-Pfalz, Germany

    • MB

      Moritz Brandt

      Attending Physician
      University Medical Center Mainz, Germany
      Mainz, Rheinland-Pfalz, Germany

    • ST

      Stefan Tenzer

      Professor
      University Medical Center Mainz, Germany
      Mainz, Rheinland-Pfalz, Germany

    • TG

      Tommaso Gori

      Professor
      University Medical Center Mainz, Germany
      Mainz, Rheinland-Pfalz, Germany

    • HM

      Hendrik Milting

      Professor
      Herz- und Diabeteszentrum NRW, Bad Oeynhausen
      Bad Oeynhausen, Nordrhein-Westfalen, Germany

    • Wolfram Ruf, MD

      Scientific Director
      University Medicine of the Johannes Gutenberg University Mainz, Center for Thrombosis and Hemostasis (CTH)
      Mainz, Rheinland-Pfalz, Germany

      • Presenting Author(s)

    • Philip Wenzel, MD (he/him/his)

      Professor
      Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz
      Mainz, Rheinland-Pfalz, Germany

    Background: Despite major advances in acute interventions of myocardial infarction (MI), adverse cardiac remodeling and excess fibrosis post MI causing ischemic heart failure (IHF) remains a leading cause of death worldwide.

    Aims: We aimed to identify novel molecular switches that could be targeted to tackle thrombo-inflammation and to prevent the development of IHF after MI

    Methods: Myocardial specimens from severe IHF patients and healthy donors were compared using (phospho)proteome analysis and Western blotting. Permanent ligation of the left anterior descending coronary artery was performed to induce unreperfused MI in mice and to study the development of IHF. Echocardiography, confocal microscopy, flow-cytometry and (immuno) histochemistry were used to analyse MI and IHF in mice, employing bone marrow chimera studies as well as pharmacological and genetic tools to dissect myeloid cell specific thrombo-inflammatory signalling pathways.

    Results: Quantitative phospho-proteomics of cardiac tissue revealed an up-regulated 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 pro-fibrotic transforming growth factor β1 (TGF-β1). Specific targeting with the TF inhibitor nematode anticoagulant protein c2 (NAPc2) starting one day after established experimental MI averts IHF. Increased TF cytoplasmic domain phosphorylation in circulating monocytes from patients with sub-acute MI identifies a potential thrombo-inflammatory biomarker reflective of increased risk for IHF and suitable for patient selection to receive targeted TF inhibition therapy.

    Conclusion(s): We identifed a novel pro-fibrotic coagulation signaling pathway that can be targeted for improved cardiac function following MI with persistent ischemia.

    Learning Objectives:

    • appreciate the coagulation-inflammation signaling in myeloid cells accumulating in the heart after an MI
    • realize that this specific role may be a druggable target to prevent excess fibrosis and heart failure in ischemic heart disease
    • translate findings in mouse models of unreperfused MI to the clinical scenario of subacute MI with delayed reperfuion