Plasminogen Activator Inhibitor-1 Promotes Neutrophil Infiltration and Tissue Injury on Ischemia–Reperfusion

• DOI: 10.1161/atvbaha.117.309760
• Publication Date: 2018-01-25T10:00:09Z
• Authors: Marc Praetner; Gabriele Zuchtriegel; Martin Holzer; Bernd Uhl; Johanna Schaubächer; Laura Mittmann; Matthias Fabritius; Robert Fürst; Stefan Zahler; Dominik Funken; Maximilian Lerche...; Andrej Khandoga; Sandip Kanse; Kirsten Lauber; Fritz Krombach; Christoph A. Reichel
• Keywords: Plasminogen activator inhibitor-1

Objective— Ischemia–reperfusion (I/R) injury significantly contributes to organ dysfunction and failure after myocardial infarction, stroke, transplantation. In addition its established role in the fibrinolytic system, plasminogen activator inhibitor-1 has recently been implicated pathogenesis of I/R injury. The underlying mechanisms remain largely obscure. Approach Results— Using different vivo microscopy techniques as well ex analyses vitro assays, we identified that rapidly accumulates on microvascular endothelial cells enabling this protease inhibitor exhibit previously unrecognized functional properties by inducing an increase affinity β2 integrins intravascularly rolling neutrophils. These events are mediated through low-density lipoprotein receptor–related protein-1 mitogen-activated protein kinase–dependent signaling pathways initiate intravascular adherence these immune endothelium. Subsequent process, extravasating neutrophils disrupt junctions promote postischemic leakage. Conversely, deficiency effectively reversed leukocyte infiltration, dysfunction, tissue experimental without exhibiting side effects hemostasis. Conclusions— Our data provide novel insights into nonfibrinolytic system emphasize a promising target for prevention treatment