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December 2022

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Targeting myeloid cell coagulation signaling blocks MAP kinase/TGF-beta1 driven fibrotic remodeling in ischemic heart failure. DZHK authors: V. Garlapati, M. Molitor, S. Finger, J. Wild, S. Karbach, T. Münzel, A. Daiber, M. Brandt, T. Gori, S. Tenzer, W. Ruf, P. Wenzel. J Clin Invest (2022). doi: 10.1172/JCI156436

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In this study, the DZHK researchers around Prof. Philip Wenzel and Prof. Wolfram Ruf at the Center for Thrombosis and Hemostasis at the Rhein-Main partner site documented proteome changes in the hearts of patients with ischemic heart failure (IHF), which not only showed an upregulated MAPK pathway, but also prominent features of coagulation and activation of the innate immune response.

Using genetic and pharmacological approaches in a mouse model of IHF, they were able to show that MAPK activation in myocardial infarction (MI) requires myeloid cell signaling of protease-activated receptor 2 (PAR2) conjugated with the cytoplasmic domain of tissue factor (TF). They act upstream of pro-oxidative NOX2-NADPH oxidase, ERK1/2 phosphorylation and activation of pro-fibrotic transforming growth factor beta1 (TGF-b1). The data provide new insights into potential therapeutic targets for prevention and treatment of IHF, which can be exploited, for example, by the TF inhibitor nematode anticoagulant protein c2 (NAPC2), starting one day after an MI has occurred.

In addition, the authors identified a marker on circulating monocytes from patients with subacute myocardial infarction, i.e. patients at risk for developing IHF. This marker precisely indicated the pro-fibrotic coagulation signaling pathway, which appears to be mechanistically crucial in the development of IHF. The work combines translation from clinical discovery through preclinical target validation to development of a diagnostic strategy to identify patients for targeted therapies after MI.

Original publication