Modification of Post-Myocardial Infarction Granulocyte-Colony Stimulating Factor Therapy With Myelosuppressives

Abstract

BackgroundThe purpose of the present study was to investigate the effect of granulocyte colony-stimulating factor (G-CSF) in combination with myelosuppressives on post-myocardial infarction (MI) myocardial repair. Methods and Results Twenty-four hours after 30-min ischemia and reperfusion (day 0), rabbits were assigned to 4 treatment groups: myelosuppressives (M group), G-CSF (G group), the 2 in combination (MG group) or saline (S group). Significantly greater numbers of circulating stem cells were seen in the MG group than in the G group, with attenuated leukocytosis. In addition, MG caused the greatest upregulation of stromal cell-derived factor (SDF)-1 within the infarcted myocardium and thus recruitment of stem cells from the circulation into the infarcted tissue. This led to enhanced myocardial repair, as indicated by the numbers of bone marrow cell-derived cardiomyocytes and endothelial cells, reduction in scar tissue, improvement in cardiac function and reduction in left ventricular remodeling during the chronic phase of MI. These beneficial effects were entirely abolished by the administration of a CXCR4 antagonist AMD3100, which indicates the importance of CXCR4/SDF-1-axis as a mechanism underlying myocardial repair. Conclusion The combination of G-CSF and myelosuppressives may be a useful new therapy that overcomes the insufficiency seen with G-CSF alone. (Circ J 2007; 71: 580 -590)

Effects of CXCR4 Gene Transfer on Cardiac Function After Ischemia-Reperfusion Injury

“…These results suggested that the CXCR4/CXCL12 axis plays a critical role in the beneficial effects of G-CSF via recruitment of CXCR4 ϩ progenitor cells into the infarcted myocardium. 36,37 However, we have also demonstrated that activation of CXCR4 decreased papillary muscle and cardiac myocyte contractility in response to Ca 2ϩ and isoproterenol in vitro. 15 The negative inotropic effects on the heart may benefit cardiomyocyte survival and preserve heart function in ischemia and reperfusion injury.…”

“…[33][34][35] Administration of granulocyte-colony stimulating factor (G-CSF) after MI improves LV function and reduces LV remodeling and infarct size. 36,37 These beneficial effects of G-CSF were entirely abolished by the specific CXCR4 antagonist AMD3100. These results suggested that the CXCR4/CXCL12 axis plays a critical role in the beneficial effects of G-CSF via recruitment of CXCR4 ϩ progenitor cells into the infarcted myocardium.…”

Development of novel CXCR4-based therapeutics

“…Interestingly, these beneficial effects were entirely abolished by the administration of a CXCR4 antagonist AMD3100, which can both mobilize stem cells from the bone marrow and block entry of these cells into tissues. This indicates the importance and complexity of using CXCR4 antagonists for repair [113].…”

Treatment With Recombinant Placental Growth Factor (PlGF) Enhances Both Angiogenesis and Arteriogenesis and Improves Survival After Myocardial Infarction

“…Earlier experimental studies have shown that several growth factors and cytokines, including basic fibroblast growth factor, 18 G-CSF, 19 erythropoietin, 20 angiopoietin-1 21 and VEGF, 22 improve cardiac function after AMI by promoting angiogenesis. However, no molecule has been clinically proved to be useful as an adjunctive therapy in AMI.…”