Marc Praetner1, Gabriele Zuchtriegel1, Martin Holzer1, Bernd Uhl1, Johanna Schaubächer1, Laura Mittmann1, Matthias Fabritius1, Robert Fürst1, Stefan Zahler1, Dominik Funken1, Maximilian Lerchenberger1, Andrej Khandoga1, Sandip Kanse1, Kirsten Lauber1, Fritz Krombach1, Christoph A Reichel2. 1. From the Walter Brendel Centre of Experimental Medicine (M.P., G.Z., M.H., B.U., J.S., L.M., M.F., D.F., M.L., A.K., F.K., C.A.R.), Department of Otorhinolaryngology (G.Z., M.H., B.U., C.A.R.), Head and Neck Surgery (M.P.), Pharmaceutical Biology, Department of Pharmacy, Center for Drug Research (S.Z.), Department of Surgery (D.F., M.L., A.K.), and Department of Radiation Oncology (K.L.), Ludwig-Maximilians-Universität München, Munich, Germany; Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Germany (M.P); Institute of Pharmaceutical Biology, Goethe University Frankfurt, Germany (R.F.); and Institute of Basic Medical Sciences, University of Oslo, Norway (S.K.). 2. From the Walter Brendel Centre of Experimental Medicine (M.P., G.Z., M.H., B.U., J.S., L.M., M.F., D.F., M.L., A.K., F.K., C.A.R.), Department of Otorhinolaryngology (G.Z., M.H., B.U., C.A.R.), Head and Neck Surgery (M.P.), Pharmaceutical Biology, Department of Pharmacy, Center for Drug Research (S.Z.), Department of Surgery (D.F., M.L., A.K.), and Department of Radiation Oncology (K.L.), Ludwig-Maximilians-Universität München, Munich, Germany; Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Germany (M.P); Institute of Pharmaceutical Biology, Goethe University Frankfurt, Germany (R.F.); and Institute of Basic Medical Sciences, University of Oslo, Norway (S.K.). christoph.reichel@med.uni-muenchen.de.
Abstract
OBJECTIVE: Ischemia-reperfusion (I/R) injury significantly contributes to organ dysfunction and failure after myocardial infarction, stroke, and transplantation. In addition to its established role in the fibrinolytic system, plasminogen activator inhibitor-1 has recently been implicated in the pathogenesis of I/R injury. The underlying mechanisms remain largely obscure. APPROACH AND RESULTS: Using different in vivo microscopy techniques as well as ex vivo analyses and in vitro assays, we identified that plasminogen activator inhibitor-1 rapidly accumulates on microvascular endothelial cells on I/R enabling this protease inhibitor to exhibit previously unrecognized functional properties by inducing an increase in the affinity of β2 integrins in intravascularly rolling neutrophils. These events are mediated through low-density lipoprotein receptor-related protein-1 and mitogen-activated protein kinase-dependent signaling pathways that initiate intravascular adherence of these immune cells to the microvascular endothelium. Subsequent to this process, extravasating neutrophils disrupt endothelial junctions and promote the postischemic microvascular leakage. Conversely, deficiency of plasminogen activator inhibitor-1 effectively reversed leukocyte infiltration, microvascular dysfunction, and tissue injury on experimental I/R without exhibiting side effects on microvascular hemostasis. CONCLUSIONS: Our experimental data provide novel insights into the nonfibrinolytic properties of the fibrinolytic system and emphasize plasminogen activator inhibitor-1 as a promising target for the prevention and treatment of I/R injury.
OBJECTIVE:Ischemia-reperfusion (I/R) injury significantly contributes to organ dysfunction and failure after myocardial infarction, stroke, and transplantation. In addition to its established role in the fibrinolytic system, plasminogen activator inhibitor-1 has recently been implicated in the pathogenesis of I/R injury. The underlying mechanisms remain largely obscure. APPROACH AND RESULTS: Using different in vivo microscopy techniques as well as ex vivo analyses and in vitro assays, we identified that plasminogen activator inhibitor-1 rapidly accumulates on microvascular endothelial cells on I/R enabling this protease inhibitor to exhibit previously unrecognized functional properties by inducing an increase in the affinity of β2 integrins in intravascularly rolling neutrophils. These events are mediated through low-density lipoprotein receptor-related protein-1 and mitogen-activated protein kinase-dependent signaling pathways that initiate intravascular adherence of these immune cells to the microvascular endothelium. Subsequent to this process, extravasating neutrophils disrupt endothelial junctions and promote the postischemic microvascular leakage. Conversely, deficiency of plasminogen activator inhibitor-1 effectively reversed leukocyte infiltration, microvascular dysfunction, and tissue injury on experimental I/R without exhibiting side effects on microvascular hemostasis. CONCLUSIONS: Our experimental data provide novel insights into the nonfibrinolytic properties of the fibrinolytic system and emphasize plasminogen activator inhibitor-1 as a promising target for the prevention and treatment of I/R injury.
Authors: Ioanna Andreadou; Hector A Cabrera-Fuentes; Yvan Devaux; Nikolaos G Frangogiannis; Stefan Frantz; Tomasz Guzik; Elisa A Liehn; Clarissa P C Gomes; Rainer Schulz; Derek J Hausenloy Journal: Cardiovasc Res Date: 2019-06-01 Impact factor: 10.787
Authors: Hong S Lu; Ann Marie Schmidt; Robert A Hegele; Nigel Mackman; Daniel J Rader; Christian Weber; Alan Daugherty Journal: Arterioscler Thromb Vasc Biol Date: 2019-12-23 Impact factor: 8.311
Authors: Bernd Uhl; Laura A Mittmann; Julian Dominik; Roman Hennel; Bojan Smiljanov; Florian Haring; Johanna B Schaubächer; Constanze Braun; Lena Padovan; Robert Pick; Martin Canis; Christian Schulz; Matthias Mack; Ewgenija Gutjahr; Peter Sinn; Jörg Heil; Katja Steiger; Sandip M Kanse; Wilko Weichert; Markus Sperandio; Kirsten Lauber; Fritz Krombach; Christoph A Reichel Journal: EMBO Mol Med Date: 2021-05-16 Impact factor: 12.137