on March 30, 2006
Published online before print March 30, 2006, doi: 10.1161/01.ATV.0000219697.99134.10
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Submitted on October 12, 2005
Accepted on March 9, 2006
Granulocyte Colony Stimulating Factor Directly Inhibits Myocardial Ischemia-Reperfusion Injury Through Akt-Endothelial NO Synthase Pathway
Kazutaka Ueda ;
From the Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Japan.
* To whom correspondence should be addressed. E-mail: komuro-tky{at}umin.ac.jp.
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.
Methods and 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, 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 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.
Key words: G-CSF • reperfusion injury • cytokine • nitric oxide synthase • signal transduction
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