Erythropoietin reportedly has beneficial effects on the heart after myocardial infarction, but the underlying mechanisms of these effects are unknown. We here demonstrate that sonic hedgehog is a critical mediator of erythropoietin-induced cardioprotection in mice. Treatment of mice with erythropoietin inhibited left ventricular remodeling and improved cardiac function after myocardial infarction, independent of erythropoiesis and the mobilization of bone marrow-derived cells. Erythropoietin prevented cardiomyocyte apoptosis and increased the number of capillaries and mature vessels in infarcted hearts by upregulating the expression of angiogenic cytokines such as VEGF and angiopoietin-1 in cardiomyocytes. Erythropoietin also increased the expression of sonic hedgehog in cardiomyocytes, and inhibition of sonic hedgehog signaling suppressed the erythropoietin-induced increase in angiogenic cytokine expression. Furthermore, the beneficial effects of erythropoietin on infarcted hearts were abolished by cardiomyocyte-specific deletion of sonic hedgehog. These results suggest that erythropoietin protects the heart after myocardial infarction by inducing angiogenesis through sonic hedgehog signaling.

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...

These findings suggest that G-CSF improves cardiac function of chronic myocardial ischemia through decreases in fibrosis and apoptotic death and an increase in vascular density in the ischemic region.

Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic cytokine that promotes proliferation and differentiation of neutrophil progenitors. G-CSF also possesses immunomodulatory properties. G-CSF-induced hematopoietic stem cell mobilization is widely used clinically for transplantation. After it was recently reported that G-CSF mobilizes bone marrow stem cells (BMSCs) into the infarcted hearts and accelerates the differentiation into vascular cells and cardiac myocytes, myocardial regeneration utilizing mobilization of BMSCs by G-CSF is attracting the attention of investigators. In animal models, G-CSF prevents left ventricular remodeling and dysfunction after acute myocardial infarction, at least in part, through a decrease in apoptotic cells and an increase in vascular cells. Although it is controversial whether BMSCs mobilized by G-CSF can differentiate into cardiac myocytes, G-CSF-induced angiogenesis is indeed recognized in infarcted heart. The cardioprotective effects of G-CSF are recognized even in isolated perfused heart. In addition, G-CSF activates various signaling pathways such as Akt, extracellular signal-regulated kinase, and Janus kinase 2/signal transducer and activator of transcription 3 through G-CSF receptors in cardiac myocytes. These observations suggest that G-CSF not only induces mobilization of stem cells and progenitor cells but also acts directly on cardiomyocytes. Therefore, G-CSF may be utilized as a novel agent to have protective and regenerative effects on injured myocardium. Although the effects of G-CSF on the progression of atherosclerosis are still unclear, there is a possibility that G-CSF will become a promising therapy for ischemic heart diseases.

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