Granulocyte Colony-Stimulating Factor Reduces Cardiomyocyte Apoptosis and Improves Cardiac Function in Adriamycin-Induced Cardiomyopathy in Rats
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Background: Cardiomyocyte apoptosis reportedly participates in the occurrence and progression of dilated cardiomyopathy (DCM). Recent studies have shown that granulocyte colony-stimulating factor (G-CSF) enhances bone marrow cells migration to the damaged heart in the DCM model and improves the ultrastructure of the cardiomyocyte in adriamycin (ADR) induced DCM. However, its influence on cardiac pump function and cardiomyocyte apoptosis has not been studied.
Methods and materials: Wistar Rats were randomly grouped into control, ADR, ADR+PBS, ADR+G-CSF group (n = 10). ADR (2.5 mg/kg, 6 times for 2 weeks) was administered intraperitoneally in all rats except the control group. After 2 weeks, the rats in ADR+G-CSF group were injected with G-CSF (50 microg/kg/day for 8 days) subcutaneously. Cardiac function was evaluated by echocardiogram and cardiac catheterization after 4 weeks. Cardiomyocytes apoptosis and apoptosis-related protein Fas were detected by in situ terminal deoxynucleotidyl transferase assay (TUNEL method) and Western blot, respectively.
Results: The ADR and ADR+PBS groups showed significant deteriorations of left ventricular functions and high cardiomyocyte apoptosis index, as well as high Fas expressions. Meanwhile, the ADR+G-CSF group showed significant improvement in LV function, inhibition of cardiomyocyte apoptosis compared with the ADR and ADR+Phosphate-Buffered Saline PBS group. The Fas protein expression was remarkably attenuated as well.
Conclusion: Our results suggest that administration of G-CSF inhibited cardiomyocyte apoptosis and Fas protein expression and contributes to improving cardiac pump function in vivo in ADR induced DCM rat model.
- Codd MB, Sugrue DD, Gersch BJ, et al. Epidemiology of idiopathic dilated and hypertrophic cardiomyopathy: A population-based study in Olmsted Country, Minnesota, 1975–1984. Circulation 1989;80:564–572.
- Dec GW, Fuster V. Idiopathic dilated cardiomyopathy. N Engl J Med 1994;331:1564–1575. CrossRef
- Narula J, Haider N, Virmani R, et al. Apoptosis in myocytes in end-stage heart failure. N Engl J Med 1996;335:1182–1189. CrossRef
- Olivetti G, Abbi R, Quaini F, et al. Apoptosis in the failing human heart. N Engl J Med 1997;336:1131–1141. CrossRef
- Nakamura T, Ueda Y, Guan Y, et al. Fas-mediated apoptosis in adriamycin-induced cardiomyopathy in rats:in vivo study. 2000;102(5):572–578.
- Orlic D, Kajstura J, Chimenti S, et al. Bone marrow cells regenerate infracted myocardium. Nature 2001;410:701–705. CrossRef
- Kocher AA, Schuster, Szabolcs MJ, et al. Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med 2001;7:430–436. CrossRef
- Strauer BE, Brehm M, Zeus T, et al. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 2002;106:1913–1918. CrossRef
- Assmus B, Schachinger V, Teupe C, et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI). Circulation 2002;106:3009–3017. CrossRef
- Britten MB, Abolmaali N, Assmus B, et al. Infarct remodeling after intracoronary progenitor cell treatment in patients with acute myocardial infarction (TOPCARE-AMI): mechanistic insights from serial contrast-enhanced magnetic resonance imaging. Circulation 2003;108:2212–2218. CrossRef
- Schächinger V, Assmus B, Britten MB, et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction. Final one-year results of the TOPCARE-AMI Trial. J Am Coll Cardiol 2004;44:1690–1699. CrossRef
- Ishida M, Tomita S, Nakatani T, et al. Bone marrow mononuclear cell transplantation had beneficial effects on doxorubicin-induced cardiomyopathy. J Heart Lung Transplant 2004;4:436–445. CrossRef
- Tomita S, Ishida M, Nakatani T, et al. Bone marrow is a source of regenerated cardiomyocytes in doxorubicin-induced cardiomyopathy and granulocyte colony-stimulating factor enhances migration of bone marrow cells and attenuates cardiotoxicity of doxorubicin under electron microscopy. J Heart Lung Transplant 2004;23:577–584. CrossRef
- Scorsin M, Hagege AA, Dolizy I, et al. Can cellular transplantation improve function in doxorubicin-induced heart failure? Circulation 1998;98(Suppl III):III-51–III-55.
- Yoo KJ, Li RK, Richard D, et al. Heart cell transplantation improves heart function in dilated cardiomyopathic hamsters. Circulation 2000;102:III–20.
- Orlic D, Kajstura J, Chimenti S, et al. Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc Natl Acad Sci USA 2001;98:10344–10349. CrossRef
- Maianski NA, Mul FP, Van Buul JD, et al. Granulocyte colony-stimulating factor inhibits the mitochondria-dependent activation of caspase-3 in neutrophils. Blood 2002;99:672–679. CrossRef
- Sakamoto C, Suzuki K, Hato F, et al. Anti-apoptotic effect of granulocyte colony-stimulating factor, granulocyte- macrophage colony-stimulating factor, and cyclic AMP on human neutrophils: protein synthesis-dependent and protein synthesis-independent mechanisms and the role of the Janus kinase-STAT pathway. Int J Hematol 2003;77:60–70. CrossRef
- Hasegawa T, Suzuki K, Sakamoto C, et al. Expression of the inhibitor of apoptosis (IAP) family members in human neutrophils: up-regulation of cIAP2 by granulocyte colonystimulating factor and overexpression of cIAP2 in chronic neutrophilic leukemia. Blood 2003;101:1164–1171. CrossRef
- Harada M, Qin Y, Takano H, et al. G-CSF prevents cardiac remodeling after myocardial infarction by activating the Jak-Stat pathway in cardiomyocytes. Nat Med 2005;11:305–311. CrossRef
- Ha Y, Kim YS, Cho JM, et al. Role of granulocyte-macrophage colony-stimulating factor in preventing apoptosis and improving functional outcome in experimental spinal cord contusion injury. J Neurosurg Spine 2005;2:55–61. CrossRef
- Siveski-Iliskovic N, Kaul N, Singal PK, et al. Probucol promotes endogenous antioxidants and provides protection against adriamycin-induced cardiomyopathy in rats. Circulation 1994;89:2829–2835.
- Timao Li, Singal P K, et al. Adriamycin-induced early changes in myocardial antioxidant enzymes and their modulation by probucol. Circulation 2000;102:2105.
- Singal PK, Segstro RJ, Singh RP, et al. Changes in lysosomal morphology and enzyme activities during the development of adriamycin-induced cardiomyopathy. Can J Cardiol 1985;1:139–147.
- Tong J, Ganguly PK, Singal PK, et al. Myocardial adrenergic changes at two stages of heart failure due to adriamycin treatment in rats. Am J Physiol 1991;260:H909–H916.
- Valgimigli M, Rigolin GM, Cittanti C, et al. Use of granulocyte-colony stimulating factor during acute myocardial infarction to enhance bone marrow stem cell mobilization in humans: clinical and angiographic safety profile. Eur Heart J 2005;26:1838–1845. CrossRef
- Wang Y, Tagil K, Ripa RS, et al. Effect of mobilization of bone marrow stem cells by granulocyte colony stimulating factor on clinical symptoms, left ventricular perfusion and function in patients with severe chronic ischemic heart disease. Int J Cardiol 2005;100:477–483. CrossRef
- Fukuhara S, Tomita S, Nakatani T, et al. G-CSF promotes bone marrow cells to migrate into infarcted mice heart, and differentiate into cardiomyocytes. Cell Transplant 2004;13:741–748.
- Sugano Y, Anzai T, Yoshikawa T, et al. Granulocyte colony-stimulating factor attenuates early ventricular expansion after experimental myocardial infarction. Cardiovasc Res 2005;65:446–456. CrossRef
- Minatoguchi S, Takemura G, Chen XH, et al. Acceleration of the healing process and myocardial regeneration may be important as a mechanism of improvement of cardiac function and remodeling by post-infarction granulocyte colony-stimulating factor treatment. Circulation 2004;109:2572–2580. CrossRef
- Hamamoto M, Tomita S, Nakatani T, et al. Granulocyte-colony stimulating factor directly enhances proliferation of human troponin I-positive cells derived from idiopathic dilated cardiomyopathy through specific receptors. J Heart Lung Transplant 2004;23:1430–1437. CrossRef
- Fukuhara S, Tomita S, Nakatani T, et al. Endogenous bone-marrow-derived stem cells contribute only a small proportion of regenerated myocardium in the acute infarction model. J Heart Lung Transplant 2005;24:67–72. CrossRef
- Eikan K, Yosimichi U, Tsuneyuki N, et al. Apoptosis in young rats with Adriamycin-induced cardiomyopathy—Comparison with Pirarubicin, a new anthracycline derivative. Pediatric Res 2002;51:256–259.
- Heinke MY, Yao M, Chang D, et al. Apoptosis of ventricular and atrial myocytes from pacing-induced canine heart failure. Cardiovasc Res 2001;49:127–134. CrossRef
- Yamamura T, Nakamura H, Yamamoto T, et al. Fas expression and apoptosis correlate with cardiac dysfunction in patients with dilated cardiomyopathy. Jpn Circ J 1999;63:149–154. CrossRef
- Bagchi D, Bagchi M, Hassoun EA, et al. Adriamycin-induced hepatic and myocardial lipid-peroxidation and DNA-damage, and enhanced excretion of urinary lipid metabolites in rats. Toxicology 1995;95:1–9. CrossRef
- Papadopoulou, LC, Tsiftsoglou, AS, et al. Effects of hemin on apoptosis, suppression of cytochrome C oxidase gene expression and bone marrow toxicity induced by doxorubicin (adriamycin). Biochem Pharmacol 1996;52:713–722. CrossRef
- Mizushima Y, Morikage T, Kuwahara T, et al. Effects of granulocyte colony-stimulating factor on hematopoietic injury induced by anticancer drugs in mice. J Biol Response Mod 1990;9:576–583.
- Ohtani K, Na nya T, Aoyama Y, et al. Recombinant human granulocyte colony-stimulating factor accelerates regeneration after T-2 toxin-induced hemopoietic injury and lessens lethality in mice. J Toxicol Sci 1993;18:155–166.
- Granulocyte Colony-Stimulating Factor Reduces Cardiomyocyte Apoptosis and Improves Cardiac Function in Adriamycin-Induced Cardiomyopathy in Rats
Cardiovascular Drugs and Therapy
Volume 20, Issue 2 , pp 85-91
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- dilated cardiomyopathy
- bone marrow mobilization
- granulocyte colony-stimulating factor
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- Author Affiliations
- 1. State Key Laboratory of Experimental Hematology, Institute of Hematology, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 30020, China
- 2. Tianjin Medical College, Tianjin, 30020, China
- 3. European Hospital of George Pompidou of Paris, France, Rue Leblanc 75908, Paris Cedex 15, France
- 4. State Key Laboratory of Experimental Hematology, Institute of Hematology, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 30020, China