Granulocyte Colony Stimulating Factor Directly Inhibits Myocardial Ischemia-Reperfusion Injury Through Akt–Endothelial NO Synthase Pathway

Abstract

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. Key Words: G-CSF Ⅲ reperfusion injury Ⅲ cytokine Ⅲ nitric oxide synthase Ⅲ signal transduction M yocardial infarction (MI) is the most common cause of cardiac morbidity and mortality in many countries. Reperfusion therapy is beneficial to prevent cardiomyocyte death and contractile dysfunction after MI. However, numerous studies have shown that reperfusion itself may enhance the injury, resulting in extension of infarct size after ischemia (ie, ischemia-reperfusion [IR] injury). Although ischemic preconditioning and pharmacological preconditioning mimetics strongly protect the heart against IR injury, the requirement for pretreatment has greatly limited their clinical relevance. Meanwhile, it has been reported recently that brief intermittent ischemia applied after the onset of reperfusion, termed "postconditioning," reduces myocardial injury to an extent comparable to preconditioning. 1 Various cardioprotective mechanisms have been reported including activation of reperfusion injury salvage kinases pathway consisting of phosphatidylinositol 3-kinase (PI3K)-Akt and extracellular signal-regulated kinase (ERK). 2 Therefore, pharmacological postconditioning by administration of agents that activate the reperfusion injury salvage kinase pathway seems to be beneficial to IR injury.Granulocyte colony stimulating factor (G-CSF) has been reported recently to prevent left ventricular (LV) remodeling and dysfunction after acute MI. 3-6 G-CSF is a hematopoietic cytokine that promotes proliferation and differentiation of neutrophil progenitors. Because G-CSF has been used widely to induce mobilization of hematopoietic stem cells for transplantation, and the safety has been established, G-CSF could be used to treat MI if the efficacy has been established and the mechanisms of its beneficial effects have been elu...

Therapeutic administration of IL-11 exhibits the postconditioning effects against ischemia-reperfusion injury via STAT3 in the heart

“…Recently, much attention has been paid to the cardioprotective effects of granulocyte colony stimulating factor (G-CSF). The administration of G-CSF preserves myocardium in the myocardial infarction model (11) as well as the I/R model (26). In G-CSF signaling, JAK2/STAT3 pathway has been proposed to be important in antifibrotic effects after myocardial infarction during subacute and chronic phase, whereas the Akt/NOS pathway contributes to the beneficial effect of G-CSF in I/R hearts during the acute phase (25).…”

Signal transducer and activator of transcription 3 is involved in the cardioprotective signalling pathway activated by insulin therapy at reperfusion

“…The first possibility was supported by experiments in STAT3 deficient mice, where insulin failed to phosphorylate Akt. Ueda et al [44] recently reported that granulocyte colony stimulating factor (G-CSF) activated JAK-STAT, PI3K and Akt. Use of the JAK2 inhibitor AG490 abrogated G-CSF induced phosphorylation of JAK2, STAT3, Akt; and the PI3K inhibitor LY294002 suppressed G-CSF induced phosphorylation of Akt, but not JAK2 or STAT3.…”

Hydrogen Sulfide, a Potential Cardioprotective Gas Activating a Life Span Regulator

“…Kazutaka Ueda, 1 MD, Nobuaki Fukuma, 1 MD, and Eiki Takimoto, 1 MD R eperfusion therapy is beneficial to prevent cardiomyocyte death and contractile dysfunction after myocardial infarction. However, numerous studies have shown that reperfusion itself may enhance the injury, resulting in the increase of infarct size after ischemia [ie, ischemiareperfusion (I/R) injury].…”

“…Meanwhile, it has been recently reported that brief intermittent ischemia applied after the onset of reperfusion, termed "postconditioning," reduces myocardial injury to an extent comparable to the reduction by preconditioning. 1) Various cardioprotective mechanisms of postconditioning have been proposed, and pharmacological postconditioning by the administration of agents that modulate these mechanisms seems to be beneficial in I/R injury.…”