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, IV). 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.
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.
* See also p. 219.
Mr. Arnold and Dr. Lu contributed equally to this work.
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Supported, in part, by the Canadian Institutes of Health Research.
Dr. Feng is a career investigator at Heart and Stroke Foundation of Canada and received grant support from CIHR. Dr. J. Malcolm Arnold received payment for lectures (4-6 CMR talks). The remaining authors have disclosed that they do not have any potential conflicts of interest.
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