Mechanism of the cardioprotection of rhEPO pretreatment on suppressing the inflammatory response in ischemia-reperfusion.
Erythropoietin (EPO), originally known for its role in stimulation of erythropoiesis, has recently been shown to have a dramatic protective effect in animal models of myocardial ischemia-reperfusion (I-R) injury. However, the precise mechanisms remain unclear. We tried to study the anti-inflammatory properties of recombinant human erythropoietin (rhEPO) using an in vivo myocardial I-R rat model, which was established by 30 min ligation of left descending coronary and 3 h reperfusion. rhEPO or saline solution was intraperitoneally injected 24 h before I-R insult. The infarct size was measured by triphenyltetrazolium chloride (TTC)-Evans blue technique. Myeloperoxidase (MPO) activity and tissue neutrophil infiltration were studied. Ultrastructural organizations were observed and semiquantitatively evaluated. Tumor necrosis-alpha (TNF-alpha), interleukin-6 (IL-6), and IL-10 concentrations of left ventricle were analyzed by enzyme-linked immunosorbance assays; intercellular adhesion molecule-1 (ICAM-1) by reverse-transcription polymerase chain reaction; and nuclear factor-kappa B (NF-kappaB) and activator protein 1 (AP-1) by electrophoretic mobility shift assay, respectively. We found that a single bolus injection of 5000 units/kg of rhEPO 24 h before insult remarkably reduced infarct size and neutrophil infiltration. It greatly attenuated I-R-induced NF-kappaB and AP-1 activation with decreased TNF-alpha, IL-6, and ICAM-1 production, but enhanced IL-10 production. In conclusion, the cardioprotection of EPO may be due in part to the suppression of the inflammatory response via down-regulation of NF-kappaB and AP-1 induced by I-R. IL-10 was also suggested to play a protective role through another independent mechanism involved in cardioprotection of rhEPO.
Liu
Xiaoming
X
Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Jiangsu Province, China.
Xie
Weiying
W
Liu
Pichu
P
Duan
Manlin
M
Jia
Zhen
Z
Li
Wei
W
Xu
Jianguo
J
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D004921:Erythropoietin / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D009203:Myocardial Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D009206:Myocardium / Q000201:enzymology / Q000648:ultrastructure; D020556:Neutrophil Infiltration / Q000187:drug effects*; D009687:Nuclear Proteins / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002316:Cardiotonic Agents; D009687:Nuclear Proteins; D011994:Recombinant Proteins; D004921:Erythropoietin; D009195:Peroxidase