Granulocyte colony stimulating factor directly inhibits myocardial ischemia-reperfusion injury through Akt-endothelial NO synthase pathway.
OBJECTIVE
Granulocyte colony stimulating factor (G-CSF) has been reported recently to prevent cardiac remodeling and dysfunction after acute myocardial infarction through signal transducer and activator of transcription 3 (STAT3). In this study, we examined acute effects of G-CSF on the heart against ischemia-reperfusion injury.


RESULTS
Rat hearts were subjected to global 35-minute ischemia and 120-minute reperfusion in Langendorff system with or without G-CSF (300 ng/mL). G-CSF administration was started at the onset of reperfusion. Triphenyltetrazolium chloride staining revealed that G-CSF markedly reduced the infarct size. G-CSF strongly activated Janus kinase 2 (Jak2), STAT3, extracellular signal-regulated kinase (ERK), Akt, and endothelial NO synthase (NOS) in the hearts subjected to ischemia followed by 15-minute reperfusion. The G-CSF-induced reduction in infarct size was abolished by inhibitors of phosphatidylinositol 3-kinase, Jak2, and NOS but not of mitogen-activated protein kinase kinase (MEK).


CONCLUSIONS
These results suggest that G-CSF acts directly on the myocardium during ischemia-reperfusion injury and has acute nongenomic cardioprotective effects through the Akt-endothelial NOS pathway.
Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Japan.
Kazutaka
K
Ueda
Hiroyuki
H
Takano
Hiroshi
H
Hasegawa
Yuriko
Y
Niitsuma
Yingjie
Y
Qin
Masashi
M
Ohtsuka
Issei
I
Komuro
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004789:Enzyme Activation; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction
D002316:Cardiotonic Agents; D016179:Granulocyte Colony-Stimulating Factor; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt