Effect of recombinant erythropoietin on ischemia–reperfusion-induced apoptosis in rat liver

Abstract

Ischemia-reperfusion (I/R) cannot be avoided in liver transplantation procedures, and apoptosis is a central mechanism of cell death after liver reperfusion. Protective effect of recombinant erythropoietin (rhEPO) on liver apoptosis has not been clearly investigated. This work investigated intraportal (IP) rhEPO-protective effect in a rat model of hepatic I/R-induced apoptosis and its appropriated time and dose of administration. Eight groups were included (n = 10/group): sham-operated, I/R (45 min ischemia and 2 h reperfusion), preconditioned rhEPO I/R (24 h or 30 min before ischemia), and postconditioned rhEPO I/R (before reperfusion) using two different rhEPO doses (1,000 and 5,000 IU/kg). When compared with the sham-operated group, the I/R group showed significant increase of serum levels of aspartate and alanine aminotransferases (AST, ALT), hepatic caspase-9 activity(894.99 ± 176.90 relative fluorescence units (RFU)/mg/min versus 458.48 ± 82.96 RFU/mg/min), and Fas ligand (FasL) expression, histopathological damages, and significant decrease in the antiapoptotic Bcl-xL/apoptotic Bax ratio(0.38 ± 0.21 versus 3.35 ± 0.77) rhEPO-improved ALT and AST but failed to reduce FasL expression in all groups compared with the I/R group. Thirty minutes and 24 h preconditioning with rhEPO (1,000 IU/kg) increased Bcl-xL/Bax ratio and reduced caspase-9 activity, and the same effect was observed when higher dose was given 24 h before ischemia. Preconditioning was more effective than postconditioning in improving caspase-9 activity, and no dose-dependent effect was observed. In conclusion, single IP rhEPO injection 30 min before ischemia has an advantage over rhEPO postconditioning in improving post-hepatic I/R-induced apoptosis with no additional time- and dose-dependent effects which may provide potentially useful guide in liver transplantation procedures.

Hepatocellular Heme Oxygenase-1

“…Pre-treatment with rhEPO has been shown to ameliorate hepatic IR injury; inhibition of apoptosis has been cited as a primary mechanism of this protection[23]. Warm hepatic IR leads to necrotic cell death (oncosis), and often occurs within minutes of reperfusion.…”

Milrinone-induced postconditioning reduces hepatic ischemia-reperfusion injury in rats: the roles of phosphatidylinositol 3-kinase and nitric oxide

“…Although the mechanisms responsible for ischemic PostC of the liver are not fully understood, some studies have shown that the two processes have many similarities [6][7][8]. Recent studies have demonstrated that some agents, such as adenosine A2A receptor agonist [8], rhEPO [9], and sevoflurane [10], can be used as pharmacological inducers of PostC as well as PreC. Milrinone has been shown to have PreC properties using an orthotopic liver transplantation model and warm IR injury model in rats [14,15].…”

“…Similarly, studies have demonstrated that some agents, such as adenosine A2A receptor agonist [8], recombinant erythropoietin (rhEPO) [9], and the volatile anesthetic sevoflurane [10], can be used as pharmacological inducers of PostC as well as PreC.…”

Beyond Preconditioning: Postconditioning as an Alternative Technique in the Prevention of Liver Ischemia‐Reperfusion Injury

“…Finally, Shawky et al investigated the effect of intraportal recombinant human erythropoietin (rhEPO) in a rat model of hepatic IR injury as well as its appropriate time and dose of administration [ 64 ]. Moreover, they compared preconditioning with rhEPO (24 h or 30 min before ischemia) with postconditioning with rhEPO (administering it at reperfusion).…”