Recombinant human erythropoietin preconditioning attenuates liver ischemia reperfusion injury through the phosphatidylinositol-3 kinase/AKT/endothelial nitric oxide synthase pathway.

Abstract

BACKGROUND:

The exact mechanism by which erythropoietin protects the liver from ischemia reperfusion (I/R) injury is not yet known. In the present study, we examined the role of protein kinase B (PKB/AKT) and endothelial nitric oxide synthase (eNOS) in the protective effect of recombinant human erythropoietin (rHuEPO) on I/R injury of the liver.

MATERIALS AND METHODS:

We used a liver in situ I/R model. One hundred twenty adult male Sprague-Dawley rats were divided randomly into six groups. rHuEPO and (or) LY294002 were injected in the tail vein before the operation, and its effect was assessed by measuring the serum levels of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, nitric oxide (NO), and endothelin-1 (ET-1) and by histologic analysis. The expression of erythropoietin receptor (EPOR) and eNOS was measured by real-time polymerase chain reaction. Total AKT and eNOS and phosphorylated AKT and eNOS were examined by western blot.

RESULTS:

rHuEPO dramatically attenuated the functional and morphologic injuries. The serum levels of alanine aminotransferase and lactate dehydrogenase were significantly decreased, but the amount of NO in the serum was increased in the I/R + rHuEPO group. Accordingly, rHuEPO administration significantly ameliorated the histologic damages at 6 h after reperfusion. rHuEPO significantly stimulated the phosphorylation of AKT and eNOS in the rats after liver I/R.

CONCLUSIONS:

The protective effect of rHuEPO in I/R injury is mediated via the activation of the phosphatidylinositol-3 kinase/AKT/eNOS signaling pathway, at least in part, by increasing p-AKT and p-eNOS and leads to the maintenance of an elevated level of NO.

• Authors: Wenguang Fu, Xinxin Liao, Jian Ruan, Xianghong Li, Liyan Chen, Biao Wang, Kai Wang, Jie Zhou
• Journal: The Journal of surgical research (J Surg Res) Vol. 183 Issue 2 Pg. 876-84 (Aug 2013) ISSN: 1095-8673 [Electronic] United States
• PMID: 23490139 (Publication Type: Journal Article)
• Copyright: Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.

Chemical References

• Chromones
• Enzyme Inhibitors
• Morpholines
• Recombinant Proteins
• Erythropoietin
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• L-Lactate Dehydrogenase
• Nitric Oxide Synthase Type III
• Aspartate Aminotransferases
• Alanine Transaminase
• Phosphatidylinositol 3-Kinase
• Proto-Oncogene Proteins c-akt

Topics

• Alanine Transaminase (metabolism)
• Animals
• Aspartate Aminotransferases (metabolism)
• Chromones (pharmacology)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• Erythropoietin (pharmacology, therapeutic use)
• Humans
• Ischemic Preconditioning (methods)
• L-Lactate Dehydrogenase (metabolism)
• Liver (blood supply, metabolism, pathology)
• Male
• Morpholines (pharmacology)
• Nitric Oxide Synthase Type III (metabolism)
• Phosphatidylinositol 3-Kinase (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats
• Rats, Sprague-Dawley
• Recombinant Proteins (pharmacology, therapeutic use)
• Reperfusion Injury (metabolism, pathology, prevention & control)
• Signal Transduction (drug effects, physiology)