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Granulocyte colony-stimulating factor (G-CSF) has been reported to improve cardiac function after myocardial infarction. However, whether postinfarct acute effect of G-CSF is mediated through the same signaling pathways as those of ischemic postconditioning is still unclear. We examined the postinfarct acute effect of G-CSF on myocardial infarct size and its precise molecular mechanism. Japanese white rabbits underwent 30 min of ischemia and 48 h of reperfusion. Rabbits were intravenously injected 10 [micro]g/kg of G-CSF (G-CSF group) or saline (control group) immediately after reperfusion. The wortmannin + G-CSF, PD-98059 + G-CSF, [N.sup.[omega]]-nitro-L-arginine methyl ester (L-NAME) + G-CSF, and 5-hydroxydecanoic acid sodium salt (5-HD) + G-CSF groups were respectively injected with wortmannin (0.6 mg/kg), PD-98059 (0.3 mg/kg), L-NAME (10 mg/kg), and 5-HD (5 mg/kg) 5 min before G-CSF administration. Myocardial infarct size was calculated as a percentage of the risk area of the left ventricle. Western blot analysis was performed to examine the signals such as protein kinase B (Akt), extracellular signal-regulated protein kinase (ERK), eNOS, p70S6 kinase (p70S6K), and glycogen synthase kinase-3[beta] (GSK3[beta]) in the ischemic myocardium after 48 h of reperfusion. The infarct size was significantly smaller in the G-CSF group (26.7 [+ or -] 2.7%) than in the control group (42.3 [+ or -] 4.6%). The infarct size-reducing effect of G-CSF was completely blocked by wortmannin (44.7 [+ or -] 4.8%), PD-98059 (38.3 [+ or -] 3.9%), L-NAME (42.1 [+ or -] 4.2%), and 5-HD (42.5 [+ or -] 1.7%). Wortmannin, PD-98059, L-NAME, or 5-HD alone did not affect the infarct size. Western blotting showed higher myocardial expression of phospho-Akt, phospho-ERK, phosho-eNOS, phosho-p70S6K, and phosho-GSK3[beta] at 10 min and 48 h after reperfusion in the G-CSF group than in the control group. In conclusion, postreperfusion G-CSF administration reduces myocardial infarct size via activation of phosphatidylinositol 3-kinase-Akt and ERK prosurvival signaling pathways and their downstream targets eNOS, p70S6 kinase, GSK3[beta], and mitochondrial ATP-dependent [K.sup.+] channel. granulocyte colony-stimulating factor; myocardial infarction; infarct size; protein kinase B; extracellular signal-regulated protein kinase; endothelial nitric oxide synthase; p70S6 kinase; glycogen synthase kinase-3[beta]; adenosine 5'-diphosphate-dependent potassium ion channels; reperfusion injury salvage kinase doi: 10.1152/ajpheart.00116.2010.

The insulin-sensitizing drug pioglitazone has been reported to be protective against myocardial infarction. However, its precise mechanism is unclear. Rabbits underwent 30 min of coronary occlusion followed by 48 h of reperfusion. Rabbits were assigned randomly to nine groups (n = 10 in each): the control group (fed a normal diet), pioglitazone group (fed diets containing 1 mg x [kg.sup.-1] x [day.sup.-s1] pioglitazone), pioglitazone + 5-hydroxydecanoic acid (HD) group [fed the pioglitazone diet + 5 mg/kg iv 5-HD, a mitochondrial ATP-sensitive [K.sup.+] ([K.sub.ATP]) channel blocker], pioglitazone + GW9662 group [fed the pioglitazone diet + 2 mg/kg iv GW9662, a peroxisome proliferator activated receptor (PPAR)-[gamma] antagonist], GW9662 group (fed a normal diet + iv GW9662), pioglitazone + wortmannin group [fed the pioglitazone diet + 0.6 mg/kg iv wortmannin, a phosphatidylinositol (PI)3-kinase inhibitor], wortmannin group (fed a normal diet + iv wortmannin), pioglitazone + nitro-L-arginine methyl ester (L-NAME) group [fed the pioglitazone diet + 10 mg/kg iv L-NAME, a nitric oxide synthase (NOS) inhibitor], and L-NAME group (fed a normal diet + iv L-NAME). All groups were fed the diets for 7 days. The risk area and nonrisk area of the left ventricle (LV) were separated by Evans blue dye, and the infarct area was determined by triphenyltetrazolium chloride staining. The infarct size was calculated as a percentage of the LV risk area. Western blotting was performed to assess levels of Akt and phospho-Akt and phospho-endothelial NOS (eNOS) in the myocardium following reperfusion. The infarct size was significantly smaller in the pioglitazone group (21 [+ or -] 2%) than in the control group (43 [+ or -] 3%). This effect was abolished by GW9662 (42 [+ or -] 3%), wortmannin (40 [+ or -] 3%), or L-NAME (42 [+ or -] 7%) but not by 5-HD (24 [+ or -] 5%). Western blotting showed higher levels of phospho-Akt and phospho-eNOS in the pioglitazone group. Pioglitazone reduces the myocardial infarct size via activation of PPAR-[gamma], PI3-kinase, Akt, and eNOS pathways, but not via opening the mitochondrial [K.sub.ATP] channel. Pioglitazone may be a novel strategy for the treatment of diabetes mellitus with coronary artery disease. peroxisome proliferator activated receptor-[gamma]; phosphatidylinositol 3-kinase; endothelial nitric oxide synthase; infarct size; diabetes mellitus; ischemia-reperfusion

The earlyphase tissue uptake clearance or CLsub(uptake) at steady state in rats is compared with the change in the number of granulocyte colony-stimulating factor (G-CSF) in bone marrow and the results show that the saturable uptake and elimination of Nartograstim (NTG) in rats are due to G-CSF receptor-mediated endocytosis. The change in the CL(sub uptake) responds well to the modification in the vitro NTG-binding capacity in each isolated cell.

Granulocyte-colony-stimulating factor(G-CSF) has been reported to improve cardiac function after myocardial infarction (MI). However, whether postinfarct acute effect of G-CSF is mediated through the same signaling pathways as those of ischemic postconditioning is still unclear. We examined the postinfarct acute effect of G-CSF on myocardial infarct size and its precise molecular mechanism. Japanese white rabbits underwent 30 min of ischemia and 48 h of reperfusion. Rabbits were intravenously injected 10 μg/kg of G-CSF (G-CSF group), saline (control group) immediately after reperfusion. The wortmannin+G-CSF, PD98059+G-CSF, Nω-nitro-L-arginine methyl ester (L-NAME) + G-CSF, and 5-HD+G-CSF groups were respectively injected with wortmannin(0.6mg/kg), PD98059(0.3mg/kg), L-NAME(10mg/kg) and 5-HD(5mg/kg), 5 min before G-CSF administration. Myocardial infarct size was calculated as a percentage of the risk area of the left ventricle. Western blot analysis was performed to examine the signals such as Akt, ERK, eNOS, p70S6K and GSK3β in the ischemic myocardium after 48 hours of reperfusion. The infarct size was significantly smaller in the G-CSF group (26.7±2.7%) than in the control group (42.3±4.6%). The infarct size-reducing effect of G-CSF was completely blocked by wortmannin(44.7±4.8%), PD98059(38.3±3.9%), L-NAME (42.1±4.2%) and 5-HD (42.5±1.7%). Wortmannin, PD98059, L-NAME or 5HD alone did not affect the infarct size. Western blotting showed higher myocardial expression of phospho-Akt, phospho-ERK, phosho-eNOS, phosho-p70S6K and phosho-GSK3β at 10 min and 48 hours after reperfusion in the G-CSF group than in the control group. In conclusion, postreperfusion G-CSF administration reduces myocardial infarct size via activation of PI3K-Akt and ERK prosurvival signaling pathways and their down stream targets eNOS, p70S6K, GSK3β and mitochondrial KATP channels. [ABSTRACT FROM AUTHOR]

We investigated the effect of cardiac-targeting erythropoietin (EPO)-encapsulated liposomes with sialyl Lewis(X) (SLX) on myocardial infarct (MI) size, left ventricular (LV) remodeling and function, and its molecular mechanism for repairing infarcted myocardium. In rabbits, MI was induced by 30 min of coronary occlusion followed by reperfusion. EPO-encapsulated liposomes with SLX (L-EPO group), EPO-encapsulated liposomes without SLX (L-EPO without SLX group), liposomes with SLX without EPO (L group), or saline (saline group) were intravenously administered immediately after MI. MI sizes and numbers of microvessels were assessed 14 days after MI. Prosurvival proteins and signals were assessed by Western blot analysis 2 and 14 days after MI. Confocal microscopy and electron microscopy showed the specific accumulation of liposomes with SLX in the infarcted myocardium. MI and cardiac fibrosis areas were significantly smaller in the L-EPO group than in the other groups. LV function and remodeling were improved in the L-EPO group. The number of CD31-positive microvessels was significantly greater in the L-EPO group than in the other groups. Higher expressions of EPO receptors, phosphorylated (p)Akt, pERK, pStat3, VEGF, Bcl-2, and promatrix metalloproteinase-1 were observed in the infarct area in the L-EPO group than in the other groups. EPO-encapsulated liposomes with SLX selectively accumulated in the infarct area, reduced MI size, and improved LV remodeling and function through activation of prosurvival signals and by exerting antifibrotic and angiogenic effects. EPO-encapsulated liposomes with SLX may be a promising strategy for active targeting treatment of acute MI.