Recombinant human annexin A5 inhibits proinflammatory response and improves cardiac function and survival in mice with endotoxemia

Crit Care Med. 2014 Jan;42(1):e32-41. doi: 10.1097/CCM.0b013e3182a63e01.

Abstract

Objectives: 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.

Design: Prospective experimental study.

Setting: University laboratory.

Subjects: Adult male C57BL/6 mice.

Interventions: 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.

Measurements and main 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Annexin A5 / pharmacology*
  • Dose-Response Relationship, Drug
  • Endotoxemia / drug therapy*
  • Endotoxemia / mortality
  • Endotoxemia / physiopathology
  • Heart / drug effects*
  • Heart / physiopathology
  • Humans
  • Inflammation / physiopathology
  • Inflammation / prevention & control*
  • Interleukin-1beta / blood
  • Interleukin-1beta / physiology
  • Lipopolysaccharides / pharmacology
  • Lymphocyte Antigen 96 / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / physiology
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / physiology
  • Recombinant Proteins / pharmacology
  • Toll-Like Receptor 4 / physiology
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / blood
  • Tumor Necrosis Factor-alpha / physiology

Substances

  • Annexin A5
  • Interleukin-1beta
  • Lipopolysaccharides
  • Ly96 protein, mouse
  • Lymphocyte Antigen 96
  • NF-kappa B
  • Recombinant Proteins
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • Mitogen-Activated Protein Kinases