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

Arterioscler Thromb Vasc Biol. 2018 Apr;38(4):829-842. doi: 10.1161/ATVBAHA.117.309760. Epub 2018 Jan 25.


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.

Keywords: fibrinolysis; leukocyte; mitogen-activated protein kinases; plasminogen activator inhibitor 1; reperfusion injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abdominal Muscles / blood supply*
  • Abdominal Muscles / metabolism
  • Abdominal Muscles / pathology
  • Animals
  • CD18 Antigens / metabolism
  • Capillary Permeability
  • Cell Line
  • Disease Models, Animal
  • Humans
  • Kinetics
  • Leukocyte Rolling
  • Liver / blood supply*
  • Liver / metabolism
  • Liver / pathology
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microvessels / metabolism*
  • Microvessels / pathology
  • Neutrophil Activation
  • Neutrophil Infiltration*
  • Neutrophils / metabolism*
  • Neutrophils / transplantation
  • Plasminogen Activator Inhibitor 1 / deficiency
  • Plasminogen Activator Inhibitor 1 / genetics
  • Plasminogen Activator Inhibitor 1 / metabolism*
  • Protein Conformation
  • Receptors, LDL / metabolism
  • Reperfusion Injury / metabolism*
  • Reperfusion Injury / pathology
  • Signal Transduction
  • Tumor Suppressor Proteins / metabolism


  • CD18 Antigens
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Lrp1 protein, mouse
  • Plasminogen Activator Inhibitor 1
  • Receptors, LDL
  • Tumor Suppressor Proteins