title: Activated protein C accelerates venous thrombus resolution through heme oxygenase-1 induction.
abstract: BACKGROUND
  Thrombus resolution is a complex process that involves thrombosis, leukocyte-mediated thrombolysis, and the final resolution of inflammation. Activated protein C (APC) is an anticoagulant that also possesses immunoregulatory activities.
  
  
  OBJECTIVE
  In this study, we sought to examine the effects of APC administration on thrombus resolution using a mouse model of deep vein thrombosis by ligating the inferior vena cava (IVC).
  
  
  METHODS
  The IVCs of C57BL/6 mice were ligated. Beginning on day 4 post IVC ligation, mice were injected intraperitoneally daily with APC, APC plus an heme oxygenase-1 (HO-1) inhibitor Sn-protoporphyrin IX (SnPP), SnPP alone, or vehicle control. At different time points following surgery, the thrombus-containing IVCs were weighed and then analyzed by use of biochemical assays and histology.
  
  
  RESULTS
  Venous thrombi reached maximum size on day 4 post ligation. The APC-treated group exhibited a significant reduction in thrombus weights on day 12 but not on day 7 compared with control mice. The enhanced thrombus resolution in APC-treated mice correlated with an increased HO-1 expression and a reduced interleukin-6 production. No significant difference was found in urokinase-type plasminogen activator, plasminogen activator inhibitor-1, or matrix metalloproteinase-2 and -9 between APC-treated and control mice. Coinjection of the HO-1 inhibitor SnPP abolished the ability of APC to enhance thrombus resolution.
  
  
  CONCLUSIONS
  Our data show that APC enhances the resolution of existing venous thrombi via a mechanism that is in part dependent on HO-1, suggesting that APC could be used as a potential treatment for patients with deep vein thrombosis to accelerate thrombus resolution.
authors.affiliation: Center for Vascular and Inflammatory Diseases, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: J
authors.initials: J
authors.lastname: Gabre
authors.forename: C
authors.initials: C
authors.lastname: Chabasse
authors.forename: C
authors.initials: C
authors.lastname: Cao
authors.forename: S
authors.initials: S
authors.lastname: Mukhopadhyay
authors.forename: S
authors.initials: S
authors.lastname: Siefert
authors.forename: Y
authors.initials: Y
authors.lastname: Bi
authors.forename: S
authors.initials: S
authors.lastname: Netzel-Arnett
authors.forename: R
authors.initials: R
authors.lastname: Sarkar
authors.forename: L
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004790:Enzyme Induction; D004797:Enzyme-Linked Immunosorbent Assay; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D011486:Protein C / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D060888:Real-Time Polymerase Chain Reaction; D020246:Venous Thrombosis / Q000188:drug therapy*
chemical_list: D017931:DNA Primers; D011486:Protein C; D051547:Heme Oxygenase-1
keywords: heme oxygenase-1; inflammation; protein C; thrombolytic therapy; venous thrombosis