title: Recombinant human annexin A5 inhibits proinflammatory response and improves cardiac function and survival in mice with endotoxemia.
abstract: OBJECTIVE
  Annexin A5 is a 35-kDa protein with high affinity binding to negatively charged phospholipids. However, its effects on sepsis are not known. Our aim was to study the effects of annexin A5 on myocardial tumor necrosis factor-α expression, cardiac function, and animal survival in endotoxemia.
  
  
  METHODS
  Prospective experimental study.
  
  
  METHODS
  University laboratory.
  
  
  METHODS
  Adult male C57BL/6 mice.
  
  
  METHODS
  Mice were challenged with lipopolysaccharide (4 or 20 mg/kg, i.p.) to induce endotoxemia with and without recombinant human annexin A5 treatment (5 or 10 μg/kg, i.v.). Cytokine expression and cardiac function were assessed, and animal survival was monitored.
  
  
  RESULTS
  Treatment with annexin A5 inhibited myocardial mitogen-activated protein kinase, and nuclear factor-κB activation in mice with endotoxemia. Furthermore, annexin A5-treated animals showed significant reductions in myocardial and plasma levels of tumor necrosis factor-α and interleukin-1β while cardiac function was significantly improved during endotoxemia. Additionally, 5-day animal survival was significantly improved by either an immediate or a 4-hour delayed annexin A5 treatment after lipopolysaccharide challenge. Importantly, annexin A5 dose-dependently inhibited lipopolysaccharide binding to a toll-like receptor-4/myeloid differentiation factor 2 fusion protein.
  
  
  CONCLUSIONS
  Annexin A5 treatment decreases cytokine expression and improves cardiac function and survival during endotoxemia. These effects of annexin A5 are mediated by its ability to inhibit lipopolysaccharide binding to toll-like receptor-4, leading to reductions in mitogen-activated protein kinase and Akt signaling. Our study suggests that annexin A5 may have therapeutic potential in the treatment of sepsis.
authors.affiliation: 1Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada. 2Centre for Critical Illness Research, Lawson Health Research Institute, London, ON, Canada. 3Department of Genetics, The Scripps Research Institute, La Jolla, CA. 4Department of Medicine, University of Western Ontario, London, ON, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Arnold
authors.forename: Xiangru
authors.initials: X
authors.lastname: Lu
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Amirahmadi
authors.forename: Katharina
authors.initials: K
authors.lastname: Brandl
authors.forename: J Malcolm O
authors.initials: JM
authors.lastname: Arnold
authors.forename: Qingping
authors.initials: Q
authors.lastname: Feng
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019446:Endotoxemia / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D007249:Inflammation / Q000503:physiopathology / Q000517:prevention & control*; D053583:Interleukin-1beta / Q000097:blood / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051218:Lymphocyte Antigen 96 / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000097:blood / Q000502:physiology
chemical_list: D017304:Annexin A5; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; C411728:Ly96 protein, mouse; D051218:Lymphocyte Antigen 96; D016328:NF-kappa B; D011994:Recombinant Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases