title: 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.
  
  
  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.affiliation: Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Wenguang
authors.initials: W
authors.lastname: Fu
authors.forename: Xinxin
authors.initials: X
authors.lastname: Liao
authors.forename: Jian
authors.initials: J
authors.lastname: Ruan
authors.forename: Xianghong
authors.initials: X
authors.lastname: Li
authors.forename: Liyan
authors.initials: L
authors.lastname: Chen
authors.forename: Biao
authors.initials: B
authors.lastname: Wang
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004921:Erythropoietin / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D019194:Ischemic Preconditioning / Q000379:methods*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D011994:Recombinant Proteins; D004921:Erythropoietin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D007770:L-Lactate Dehydrogenase; D052250:Nitric Oxide Synthase Type III; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt
keywords: Endothelial nitric oxide synthase; Ischemia/reperfusion; Liver; Protein kinase B; Recombinant human erythropoietin