Hepatocellular Heme Oxygenase-1

Abstract

Hepatic ischemia-reperfusion (IR) results in progressive injury, initiated by oxidative stress during ischemia and compounded by cytokine-mediated inflammation during reperfusion. Recovery requires strict regulation of these events. Recombinant human erythropoietin (rhEPO) is thought to mitigate hepatocellular IR injury by altering the non-parenchymal liver microenvironment. This study sought to identify additional mechanisms whereby rhEPO is protective after liver IR injury. Methods Mice were treated with rhEPO (4units/gm SQ) at the onset of partial liver ischemia and assessed for transaminase and histologic injury at intervals after reperfusion. Induction of cytokines, activation of signal transducers and activators of transcription (STATs), suppressors of cytokine signaling (Socs1, Socs3, Cis), caspase-3 activation, and heme oxygenase-1 (HO-1) expression were assessed in post-ischemic liver. Effects of rhEPO stimulation were further characterized in whole liver lysates from mice undergoing rhEPO injection alone and in cultured AML-12 hepatocytes. Results rhEPO treatment at the onset of severe (90min) hepatic IR confirmed commensurate biochemical and histological protection without affecting tissue cytokine levels. Although Socs3 and STAT5 activation were induced in normal liver after in vivo rhEPO injection, this treatment did not augment expression beyond that seen with IR alone, and neither was induced in cultured hepatocytes treated with rhEPO. rhEPO inhibited caspase-3 activation in non-parenchymal cells, while hepatocellular HO-1 was rapidly induced both in vivo and in vitro with rhEPO treatment. Conclusion These data suggest HO-1 as a potent mechanism of rhEPO-mediated protection after liver IR, which involves both direct hepatocellular and non-parenchymal mechanisms.

Erythropoietin Protects Against Exertional Rhabdomyolysis-induced Acute Kidney Injury in Association with Preferential M2 Macrophage Polarization and Hemeoxygenase-1 Activation

“…In this regard, previous studies demonstrated the stimulating effect of EPO on HO1 expression in hepatocytes after ischemia/reperfusion injury [45] , neurons [46] , astrocytes [47] and in monocyte of patient under hemodialysis [48] . Moreover, the stimulatory effect of EPO on renal HO1 expression has been described in vivo and in vitro [49] , in addition to the stimulatory effect of HO1 on differentiation of M2 macrophages in models of protection against obesity-induced inflammation [50] , diabetic cardiomypathy [51] , diabetic gastroparesis [52] , colonic inflammation [53] and atherosclerosis [54] .…”

Effects of erythropoietin in neonates with hypoxic-ischemic encephalopathy receiving therapeutic hypothermia

“…Hepatic IR injuries attenuated by EPO administration before 7 and after 19 IR procedures have been reported in animal models. In the current study, the TH+EPO group had a relatively higher GOT level on day 1.…”

“…To clarify EPO's ability to restore myocardial function, a prospective study with regular and longer follow-ups of CK and CK-MB levels and cardiac echogram is required. Hepatic IR injuries attenuated by EPO administration before 7 and after 19 IR procedures have been reported in animal models. In the current study, the TH+EPO group had a relatively higher GOT level on day 1.…”

Potential Use of Biological Proteins for Liver Failure Therapy

“…In addition to erythropoiesis, it is well known that EPO has multiple protective effects and exhibits antiapoptotic, antioxidant, and anti-inflammatory activities as well ( Figure 3 ). Taking advantage of these biological activities of EPO, a number of researchers showed the protective effect of EPO in hepatic ischemia/reperfusion injury [ 84 , 85 , 86 ] that is mediated via the activation of the phosphatidylinositol-3 kinase/AKT/endotherial NO synthase pathway [ 84 ] or the inhibition of caspase-3 activation [ 85 ]. EPO also attenuates systemic ischemia/reperfusion injuries, such as liver and kidney, induced by resuscitation from a massive hemorrhage [ 87 , 88 ].…”