Yuriko Niitsuma

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.

Sonic hedgehog is a critical mediator of erythropoietin-induced cardiac protection in mice

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.

Effects of G-CSF on left ventricular remodeling and heart failure after acute myocardial infarction

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.

Amelioration of Hypertensive Heart Failure by Amlodipine May Occur via Antioxidative Effects

Although recent clinical studies have suggested that long-acting calcium channel blockers (CCBs) have beneficial effects on heart failure, the precise mechanism is unknown. In this study, Dahl salt-sensitive rats fed a high salt diet were treated with the long-acting CCB amlodipine, the low–molecular-weight membrane permeable superoxide dismutase mimetic 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl (Tempol), or saline from 11 weeks after birth. The cardiac geometry and function, and gene expression profiles were determined at 17 weeks. Dahl salt-sensitive rats fed a high salt diet followed by saline as a non-treatment control (HS group) showed a marked increase in blood pressure and developed concentric hypertrophy at 11 weeks, followed by left ventricular (LV) dilation and congestive heart failure by 17 weeks. The treatment with amlodipine (AMLO group) or Tempol (TEMP group) significantly inhibited the development of LV hypertrophy and cardiac dysfunction. Analysis using an Affymetrix GeneChip U34 revealed that the expression levels of 195 genes were changed by the treatment with amlodipine. Among these 195 genes, 110 genes were increased in HS rats and decreased in AMLO rats. And of these 110 genes, 54 genes were also decreased in TEMP rats. In contrast, 85 genes were decreased in HS rats and increased in AMLO rats. Of these 85 genes, 38 genes were also increased in TEMP rats. Approximately 48% of the genes were changed in similar fashion in AMLO and TEMP rats, suggesting that amlodipine shows beneficial effects on heart failure mainly via antioxidative mechanisms.

Efficacy of Elective Intra-aortic Balloon Pump Therapy for High-Risk Off-Pump Coronary Artery Bypass: A Prospective Comparative Study

OBJECTIVE This study evaluated the usefulness of elective intra-aortic balloon pumping (IABP) in high-risk off-pump coronary artery bypass grafting (OPCAB). MATERIALS AND METHODS From October 2002 through September 2006, total of 143 patients were operated with OPCAB. These patients were divided into two groups and clinical outcomes were compared: Group E (N = 30): Elective IABP group and Group C (N = 113): Control group, OPCAB without IABP. The criteria of elective application of IABP were severe stenosis of left main coronary artery (LMCA) or left ventricular dysfunction with an ejection fraction of less than 35%. RESULTS No significant difference was noted in the duration of ICU stay (Group E: 1.13 ± 0.43 days; Group C: 1.18 ± 0.60 days, p = 0.710), the number of patients on a respirator for 24 hours or longer after surgery (Group E: 10.0%; Group C: 5.3%, p = 0.397), hospital mortality (Group E: 0%; Group C: 0%), or the frequency of postoperative major complications between two groups. CONCLUSIONS The outcomes of OPCAB using elective IABP in high-risk patients, such as those with severe LMCA stenosis or left ventricular dysfunction, were similar to those of OPCAB in low-risk patients, suggesting the usefulness of elective IABP in OPCAB.