biostudies-literatureGarlapati VBMBFGerman Research FoundationGerman Center for Cardiovascular ResearchElse-Kröner-Fresenius-FoundationBoehringer-Ingelheim-FoundationAlexander-von-Humboldt Foundatione156436https://www.ebi.ac.uk/biostudies/studies/S-EPMC9927945biostudies-literatureUnknown133(4)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 tissThe Journal of clinical investigationTargeting myeloid cell coagulation signaling blocks MAP kinase/TGF-β1-driven fibrotic remodeling in ischemic heart failure.PMC9927945N/AAvH Ruf01EO1003,01EO1503371/47-1 FUGG,WE4361/7-1,KA-4035/1-1Munzel TRuf WHarms GSKnorr MVujacic-Mirski KWenzel PDaiber ALagrange JGori TGarlapati VFinger SMichna TBrandt MTenzer SWild SKarbach SEfentakis PMolitor MMilting HWild JJung RfalseTargeting myeloid cell coagulation signaling blocks MAP kinase/TGF-β1-driven fibrotic remodeling in ischemic heart failure.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 tiss2023-01-01T00:00:00Z2023 Feb2026-05-28T11:30:01.786Z2025-02-19T03:26:38.138ZS-EPMC99279453654806210.1172/JCI156436