title: Heparin protects against septic mortality via apoE-antagonism.
abstract: BACKGROUND
  Apolipoprotein E (apoE), a component of plasma lipoproteins, increases septic mortality in a rodent model of sepsis, presumably by enhancing lipid antigen presentation to antigen-presenting cells via the low-density lipoprotein receptor (LDLR). Downstream, this culminates in natural killer T (NKT) cell activation and cytokine secretion. To determine whether apoE antagonism would protect against septic mortality in mice, apoE-LDLR binding was antagonized using heparin, which can inhibit apoE's LDLR-binding site.
  
  
  METHODS
  C57BL/6 mice underwent cecal ligation and puncture (CLP) and heparin infusion. Serum partial thromboplastin time and alanine aminotransferase were measured at 24 hours, and survival was monitored for 7 days after CLP. LDLR+/+ and LDLR-/- fibroblasts were incubated with apoE and heparin to measure apoE internalization. Hepatic NKT cells and cytokine levels were quantified via fluorescence-activated cell sorting.
  
  
  RESULTS
  Heparin decreased CLP-induced mortality by 50% versus saline-treated controls, independent of anticoagulation. LDLR+/+ fibroblasts displayed decreased uptake of apoE when treated concurrently with heparin for 12 hours. In septic mice, hepatic alanine aminotransferase levels, hepatic NKT cells, and plasma cytokine levels decreased after heparin treatment.
  
  
  CONCLUSIONS
  This study demonstrates that heparin protects against septic mortality independent of its anticoagulant effect. This protective effect is associated with the inhibition of apoE-LDLR binding, diminished NKT proliferation and cytokine production, and hepatic dysfunction. These findings indicate a potential clinical role for apoE antagonism in the treatment of sepsis.
authors: Department of Surgery, University of California, San Francisco-East Bay, Oakland, CA, USA.
authors: Kelley I
authors: KI
authors: Chuang
authors: Briana
authors: B
authors: Leung
authors: Nancy
authors: N
authors: Hsu
authors: Hobart W
authors: HW
authors: Harris
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism*; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000378:metabolism; D001057:Apolipoproteins E / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002432:Cecum; D016207:Cytokines / Q000097:blood*; D004591:Electrophoresis, Polyacrylamide Gel; D005434:Flow Cytometry; D006493:Heparin / Q000008:administration & dosage / Q000494:pharmacology*; D006629:Hirudins / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism / Q000517:prevention & control; D008026:Ligation; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000378:metabolism*; D009844:Oligosaccharides / Q000494:pharmacology; D011677:Punctures; D011973:Receptors, LDL / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D000925:Anticoagulants; D001057:Apolipoproteins E; D016207:Cytokines; D006629:Hirudins; D009844:Oligosaccharides; D011973:Receptors, LDL; D011994:Recombinant Proteins; D006493:Heparin; D000410:Alanine Transaminase; C083544:lepirudin