Carbamylated erythropoietin protects the myocardium from acute ischemia/reperfusion injury through a PI3K/Akt-dependent mechanism.
BACKGROUND
Erythropoietin (EPO) and carbamylated erythropoietin (CEPO) can protect tissue from injury; however, CEPO has its protective effect in the absence of erythropoietic stimulation. The mechanism whereby CEPO protects heart from acute ischemia/reperfusion (I/R) injury remains unknown.


METHODS
BALB/c mice were subjected to myocardial ischemia for 45 min followed by reperfusion for 4 h, and they received a single dose of CEPO intraperitoneal at the onset of reperfusion. Myocardial infarct size and cardiac function were assessed. The association of erythropoietin receptor with beta common receptor (betacR) was examined. The level of Akt phosphorylation in the myocardium was assayed as well as a series of downstream target genes of PI3K/Akt,including p-GATA-4, GATA-4, MHC, and troponin I.


RESULTS
CEPO administration immediately before reperfusion decreased infarction by 40% and increased ejection fraction (27%) and fractional shortening (22%), compared with untreated ischemic hearts (P < .05 each). CEPO promoted association of the EPO receptor and betacR. Furthermore, CEPO administration increased the levels of phospho-Akt in the myocardium by 59% (P < .05). A PI3K inhibitor, wortmannin, blocked the beneficial effect of CEPO on infarct size and cardiac function and attenuated the CEPO-induced Akt phosphorylation. CEPO also increased the expression of p-GATA-4, GATA-4, myosin heavy chain, and troponin I.


CONCLUSIONS
A single dose of CEPO at the onset of reperfusion attenuated acute myocardial I/R injury in the mouse. CEPO-induced cardioprotection appears to be mediated through a PI3K/Akt-dependent mechanism.
Xu
Xuan
X
Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
Cao
Zhijuan
Z
Cao
Bin
B
Li
Jing
J
Guo
Lin
L
Que
Linli
L
Ha
Tuanzhu
T
Chen
Qi
Q
Li
Chuanfu
C
Li
Yuehua
Y
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D053648:Cytokine Receptor Common beta Subunit / Q000378:metabolism; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D050991:GATA4 Transcription Factor / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D018995:Myosin Heavy Chains / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017467:Receptors, Erythropoietin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019210:Troponin I / Q000378:metabolism; D000077191:Wortmannin
D000730:Androstadienes; D002316:Cardiotonic Agents; D053648:Cytokine Receptor Common beta Subunit; D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; D017467:Receptors, Erythropoietin; D019210:Troponin I; C488171:carbamylated erythropoietin; D004921:Erythropoietin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D018995:Myosin Heavy Chains; D000077191:Wortmannin