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Am J Surg. 2011 Sep;202(3):325-35. doi: 10.1016/j.amjsurg.2010.10.017. Epub 2011 Jul 8.

Heparin protects against septic mortality via apoE-antagonism.

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  • 1Department of Surgery, University of California, San Francisco-East Bay, Oakland, CA, USA.

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.

Copyright © 2011 Elsevier Inc. All rights reserved.

Comment in

PMID:
21741028
[PubMed - indexed for MEDLINE]
PMCID:
PMC3163763
Free PMC Article

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