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. 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 (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.