title: MMP-9 deficiency shelters endothelial PECAM-1 expression and enhances regeneration of steatotic livers after ischemia and reperfusion injury.
abstract: OBJECTIVE
  Organ shortage has led to the use of steatotic livers in transplantation, despite their elevated susceptibility to ischemia/reperfusion injury (IRI). Matrix metalloproteinase-9 (MMP-9), an inducible gelatinase, is emerging as a central mediator of leukocyte traffic into inflamed tissues. However, its role in steatotic hepatic IRI has yet to be demonstrated.
  
  
  METHODS
  We examined the function of MMP-9 in mice fed with a high-fat diet (HFD), which developed approximately 50% hepatic steatosis, predominantly macrovesicular, prior to partial hepatic IRI.
  
  
  RESULTS
  The inability of MMP-9(-/-) deficient steatotic mice to express MMP-9 significantly protected these mice from liver IRI. Compared to fatty controls, MMP-9(-/-) steatotic livers showed significantly reduced leukocyte infiltration, proinflammatory cytokine expression, and liver necrosis. Loss of MMP-9 activity preserved platelet endothelial cell adhesion molecule-1 (PECAM-1) expression, a modulator of vascular integrity at the endothelial cell-cell junctions in steatotic livers after IRI. Using in vitro approaches, we show that targeted inhibition of MMP-9 sheltered the extracellular portion of PECAM-1 from proteolytic processing, and disrupted leukocyte migration across this junctional molecule. Moreover, the evaluation of distinct parameters of regeneration, proliferating cell nuclear antigen (PCNA) and histone H3 phosphorylation (pH3), provided evidence that hepatocyte progression into S phase and mitosis was notably enhanced in MMP-9(-/-) steatotic livers after IRI.
  
  
  CONCLUSIONS
  MMP-9 activity disrupts vascular integrity at least partially through a PECAM-1 dependent mechanism and interferes with regeneration of steatotic livers after IRI. Our novel findings establish MMP-9 as an important mediator of steatotic liver IRI.
authors.affiliation: The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kato
authors.affiliation: The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States.
authors.forename: Naohisa
authors.initials: N
authors.lastname: Kuriyama
authors.affiliation: The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States.
authors.forename: Sergio
authors.initials: S
authors.lastname: Duarte
authors.affiliation: Swiss HPB (Hepato-Pancreato-Biliary) Center, Department of Surgery, University Hospital Zurich, 100 Raemistrasse, 8091 Zurich, Switzerland.
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Clavien
authors.affiliation: The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States.
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Busuttil
authors.affiliation: The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States. Electronic address: acoito@mednet.ucla.edu.
authors.forename: Ana J
authors.initials: AJ
authors.lastname: Coito
mesh_terms: D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D004730:Endothelium, Vascular / Q000378:metabolism; D007962:Leukocytes / Q000473:pathology / Q000502:physiology; D008099:Liver / Q000473:pathology / Q000503:physiopathology; D008115:Liver Regeneration / Q000235:genetics / Q000502:physiology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000473:pathology / Q000503:physiopathology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism*; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology*
chemical_list: D019408:Platelet Endothelial Cell Adhesion Molecule-1; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: Hepatic steatosis; Liver ischemia and reperfusion injury; MMP-9; PECAM-1