Skip to main content

Advertisement

SpringerLink
Log in

Granulocyte-Colony Stimulating Factor Reduces Cardiomyocyte Apoptosis and Ameliorates Diastolic Dysfunction in Otsuka Long-Evans Tokushima Fatty Rats

  • ORIGINAL ARTICLE
  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

Background

In recent studies, granulocyte-colony stimulating factor (G-CSF) was shown to improve cardiac function in myocardial infarction and non-ischemic cardiomyopathies. The mechanisms of these beneficial effects of G-CSF in diabetic cardiomyopathy are not yet fully understood. Therefore, we investigated the mechanisms of action of G-CSF on diabetic cardiomyopathy in a rat model of type 2 diabetes.

Methods

Seventeen-week-old OLETF (Otsuka Long Evans Tokushima Fatty) diabetic rats and LETO (Long Evans Tokushima Otuska) rats were randomized to treatment with 5 days of G-CSF (100 μg/kg/day) or with saline. Cardiac function was evaluated by serial echocardiography performed before and 4 weeks after treatment. We measured expression of the G-CSF receptor (GCSFR) and Bcl-2, as well as the extent of apoptosis in the myocardium.

Results

G-CSF treatment significantly improved cardiac diastolic function in the serial echocardiography assessments. Expression of G-CSFR was down-regulated in the diabetic myocardium (0.03 ± 0.12 % vs. 1 ± 0.15 %, p < 0.05), and its expression was stimulated by G-CSF treatment (0.03 ± 0.12 % vs. 0.42 ± 0.06 %, p < 0.05). In addition, G-CSF treatment increased the expression of Bcl-2 in the diabetic myocardium (0.69 ± 0.06 % vs. 0.26 ± 0.11 %, p < 0.05), consistent with the reduced cardiomyocyte apoptosis (9.38 ± 0.67 % vs. 17.28 ± 2.16 %, p < 0.05).

Conclusions

Our results suggest that G-CSF might have a cardioprotective effect in diabetic cardiomyopathy through up-regulation of G-CSFR, attenuation of apoptosis by up-regulation of Bcl-2 expression, and glucose-lowering effect. Our findings support the therapeutic potential of G-CSF in diabetic cardiomyopathy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Battiprolu PK, Gillette TG, Wang ZV, Lavandero S, Hill JA. Diabetic Cardiomyopathy: Mechanisms and Therapeutic Targets. Drug Discov Today Dis Mech. 2010;7(2):e135–e43. doi:10.1016/j.ddmec.2010.08.001.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Falcao-Pires I, Leite-Moreira AF. Diabetic cardiomyopathy: understanding the molecular and cellular basis to progress in diagnosis and treatment. Heart Fail Rev. 2012;17(3):325–44. doi:10.1007/s10741-011-9257-z.

    Article  CAS  PubMed  Google Scholar 

  3. Fiordaliso F, Li B, Latini R, Sonnenblick EH, Anversa P, Leri A, et al. Myocyte death in streptozotocin-induced diabetes in rats in angiotensin II- dependent. Lab Investig. 2000;80(4):513–27.

    Article  CAS  PubMed  Google Scholar 

  4. Frustaci A, Kajstura J, Chimenti C, Jakoniuk I, Leri A, Maseri A, et al. Myocardial cell death in human diabetes. Circ Res. 2000;87(12):1123–32.

    Article  CAS  PubMed  Google Scholar 

  5. Yoon YS, Uchida S, Masuo O, Cejna M, Park JS, Gwon HC, et al. Progressive attenuation of myocardial vascular endothelial growth factor expression is a seminal event in diabetic cardiomyopathy: restoration of microvascular homeostasis and recovery of cardiac function in diabetic cardiomyopathy after replenishment of local vascular endothelial growth factor. Circulation. 2005;111(16):2073–85. doi:10.1161/01.cir.0000162472.52990.36.

    Article  CAS  PubMed  Google Scholar 

  6. Harada M, Qin Y, Takano H, Minamino T, Zou Y, Toko H, et al. G-CSF prevents cardiac remodeling after myocardial infarction by activating the Jak-Stat pathway in cardiomyocytes. Nat Med. 2005;11(3):305–11. doi:10.1038/nm1199.

    Article  CAS  PubMed  Google Scholar 

  7. Minatoguchi S, Takemura G, Chen XH, Wang N, Uno Y, Koda M, et al. Acceleration of the healing process and myocardial regeneration may be important as a mechanism of improvement of cardiac function and remodeling by postinfarction granulocyte colony-stimulating factor treatment. Circulation. 2004;109(21):2572–80. doi:10.1161/01.cir.0000129770.93985.3e.

    Article  CAS  PubMed  Google Scholar 

  8. Huttmann A, Duhrsen U, Stypmann J, Noppeney R, Nuckel H, Neumann T, et al. Granulocyte colony-stimulating factor-induced blood stem cell mobilisation in patients with chronic heart failure–Feasibility, safety and effects on exercise tolerance and cardiac function. Basic Res Cardiol. 2006;101(1):78–86. doi:10.1007/s00395-005-0556-1.

    Article  PubMed  Google Scholar 

  9. Li L, Takemura G, Li Y, Miyata S, Esaki M, Okada H, et al. Granulocyte colony-stimulating factor improves left ventricular function of doxorubicin-induced cardiomyopathy. Lab Investig. 2007;87(5):440–55. doi:10.1038/labinvest.3700530.

    CAS  PubMed  Google Scholar 

  10. Hou XW, Son J, Wang Y, Ru YX, Lian Q, Majiti W, et al. Granulocyte colony-stimulating factor reduces cardiomyocyte apoptosis and improves cardiac function in adriamycin-induced cardiomyopathy in rats. Cardiovasc Drugs Ther. 2006;20(2):85–91. doi:10.1007/s10557-006-7652-9.

    Article  CAS  PubMed  Google Scholar 

  11. Lim YH, Joe JH, Jang KS, Song YS, So BI, Fang CH, et al. Effects of granulocyte-colony stimulating factor (G-CSF) on diabetic cardiomyopathy in Otsuka Long-Evans Tokushima fatty rats. Cardiovasc Diabetol. 2011;10:92. doi:10.1186/1475-2840-10-92.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol. 2010;8(6):e1000412. doi:10.1371/journal.pbio.1000412.

    Article  PubMed Central  PubMed  Google Scholar 

  13. Kawano K, Hirashima T, Mori S, Saitoh Y, Kurosumi M, Natori T. Spontaneous long-term hyperglycemic rat with diabetic complications. Otsuka Long-Evans Tokushima Fatty (OLETF) strain. Diabetes. 1992;41(11):1422–8.

    Article  CAS  PubMed  Google Scholar 

  14. Blom D, Yamin TT, Champy MF, Selloum M, Bedu E, Carballo-Jane E, et al. Altered lipoprotein metabolism in P2Y (13) knockout mice. Biochim Biophys Acta. 2010;1801(12):1349–60. doi:10.1016/j.bbalip.2010.08.013.

    Article  CAS  PubMed  Google Scholar 

  15. Yi-Sun S, Cheng-Hu F, Byung-Im S, Jun-Young P, Dae Won J, Kyung-Soo K. Therapeutic effects of granulocyte-colony stimulating factor on non-alcoholic hepatic steatosis in the rat. Ann Hepatol. 2013;12(1):115–22.

    Google Scholar 

  16. Demetri GD, Griffin JD. Granulocyte colony-stimulating factor and its receptor. Blood. 1991;78(11):2791–808.

    CAS  PubMed  Google Scholar 

  17. Baldo MP, Davel AP, Damas-Souza DM, Nicoletti-Carvalho JE, Bordin S, Carvalho HF, et al. The antiapoptotic effect of granulocyte colony-stimulating factor reduces infarct size and prevents heart failure development in rats. Cell Physiol Biochem. 2011;28(1):33–40. doi:10.1159/000331711.

    Article  CAS  PubMed  Google Scholar 

  18. Sato T, Suzuki H, Kusuyama T, Omori Y, Soda T, Tsunoda F, et al. G-CSF after myocardial infarction accelerates angiogenesis and reduces fibrosis in swine. Int J Cardiol. 2008;127(2):166–73. doi:10.1016/j.ijcard.2007.05.007.

    Article  PubMed  Google Scholar 

  19. Li JM, Yao ZF, Zou YZ, Ge JB, Guan AL, Wu J. The therapeutic potential of G-CSF in pressure overload induced ventricular reconstruction and heart failure in mice. Mol Biol Rep. 2012;39(1):5–12. doi:10.1007/s11033-011-0703-8.

    Article  CAS  PubMed  Google Scholar 

  20. Balsam LB, Wagers AJ, Christensen JL, Kofidis T, Weissman IL, Robbins RC. Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature. 2004;428(6983):668–73. doi:10.1038/nature02460.

    Article  CAS  PubMed  Google Scholar 

  21. Murry CE, Soonpaa MH, Reinecke H, Nakajima H, Nakajima HO, Rubart M, et al. Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature. 2004;428(6983):664–8. doi:10.1038/nature02446.

    Article  CAS  PubMed  Google Scholar 

  22. Norol F, Merlet P, Isnard R, Sebillon P, Bonnet N, Cailliot C, et al. Influence of mobilized stem cells on myocardial infarct repair in a nonhuman primate model. Blood. 2003;102(13):4361–8. doi:10.1182/blood-2003-03-0685.

    Article  CAS  PubMed  Google Scholar 

  23. Gnecchi M, He H, Liang OD, Melo LG, Morello F, Mu H, et al. Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat Med. 2005;11(4):367–8. doi:10.1038/nm0405-367.

    Article  CAS  PubMed  Google Scholar 

  24. Hamamoto M, Tomita S, Nakatani T, Yutani C, Yamashiro S, Sueda 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(12):1430–7. doi:10.1016/j.healun.2003.09.031.

    Article  PubMed  Google Scholar 

  25. Fukuhara S, Tomita S, Nakatani T, Yutani C, Kitamura S. 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(1):67–72. doi:10.1016/j.healun.2003.09.032.

    Article  PubMed  Google Scholar 

  26. Li Y, Takemura G, Okada H, Miyata S, Esaki M, Maruyama R, et al. Treatment with granulocyte colony-stimulating factor ameliorates chronic heart failure. Lab Investig. 2006;86(1):32–44. doi:10.1038/labinvest.3700367.

    Article  CAS  PubMed  Google Scholar 

  27. Dai Y, Ashraf M, Zuo S, Uemura R, Dai YS, Wang Y, et al. Mobilized bone marrow progenitor cells serve as donors of cytoprotective genes for cardiac repair. J Mol Cell Cardiol. 2008;44(3):607–17. doi:10.1016/j.yjmcc.2007.11.011.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Baraka A, AbdelGawad H. Targeting apoptosis in the heart of streptozotocin-induced diabetic rats. J Cardiovasc Pharmacol Ther. 2010;15(2):175–81. doi:10.1177/1074248409356557.

    Article  CAS  PubMed  Google Scholar 

  29. Engel D, Peshock R, Armstong RC, Sivasubramanian N, Mann DL. Cardiac myocyte apoptosis provokes adverse cardiac remodeling in transgenic mice with targeted TNF overexpression. Am J Physiol Heart Circ Physiol. 2004;287(3):H1303–11. doi:10.1152/ajpheart.00053.2004.

    Article  CAS  PubMed  Google Scholar 

  30. Kajstura J, Fiordaliso F, Andreoli AM, Li B, Chimenti S, Medow MS, et al. IGF-1 overexpression inhibits the development of diabetic cardiomyopathy and angiotensin II-mediated oxidative stress. Diabetes. 2001;50(6):1414–24.

    Article  CAS  PubMed  Google Scholar 

  31. Young ME, McNulty P, Taegtmeyer H. Adaptation and maladaptation of the heart in diabetes: Part II: potential mechanisms. Circulation. 2002;105(15):1861–70.

    Article  CAS  PubMed  Google Scholar 

  32. King GL, Wakasaki H. Theoretical mechanisms by which hyperglycemia and insulin resistance could cause cardiovascular diseases in diabetes. Diabetes Care. 1999;22 Suppl 3:C31–7.

    PubMed  Google Scholar 

  33. Cai L, Li W, Wang G, Guo L, Jiang Y, Kang YJ. Hyperglycemia-induced apoptosis in mouse myocardium: mitochondrial cytochrome C-mediated caspase-3 activation pathway. Diabetes. 2002;51(6):1938–48.

    Article  CAS  PubMed  Google Scholar 

  34. Stroncek DF, Clay ME, Petzoldt ML, Smith J, Jaszcz W, Oldham FB, et al. Treatment of normal individuals with granulocyte-colony-stimulating factor: donor experiences and the effects on peripheral blood CD34+ cell counts and on the collection of peripheral blood stem cells. Transfusion. 1996;36(7):601–10.

    Article  CAS  PubMed  Google Scholar 

  35. Kared H, Masson A, Adle-Biassette H, Bach JF, Chatenoud L, Zavala F. Treatment with granulocyte colony-stimulating factor prevents diabetes in NOD mice by recruiting plasmacytoid dendritic cells and functional CD4 (+) CD25 (+) regulatory T-cells. Diabetes. 2005;54(1):78–84.

    Article  CAS  PubMed  Google Scholar 

  36. Huang P, Li S, Han M, Xiao Z, Yang R, Han ZC. Autologous transplantation of granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cells improves critical limb ischemia in diabetes. Diabetes Care. 2005;28(9):2155–60.

    Article  PubMed  Google Scholar 

Download references

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Cardiology division, Department of Internal Medicine, Hanyang University College of Medicine, 222 Wangsipri Street, Sungdong-gu, Seoul, 133-792, Republic of Korea

    Jeong Hun Shin, Young-Hyo Lim, Yonggu Lee & Kyung-Soo Kim

  2. Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Republic of Korea

    Yi-Sun Song, Byung-Im So, Jun-Young Park & Kyung-Soo Kim

  3. Department of Internal Medicine, College of Medicine, Yanbian University, Yanji, 133000, China

    Cheng-Hu Fang

  4. Department of Thoracic and Cardiovascular Surgery, Hanyang University College of Medicine, Seoul, Republic of Korea

    Hyuck Kim

Authors
  1. Jeong Hun Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Young-Hyo Lim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yi-Sun Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Byung-Im So
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jun-Young Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Cheng-Hu Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yonggu Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hyuck Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kyung-Soo Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kyung-Soo Kim.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shin, J.H., Lim, YH., Song, YS. et al. Granulocyte-Colony Stimulating Factor Reduces Cardiomyocyte Apoptosis and Ameliorates Diastolic Dysfunction in Otsuka Long-Evans Tokushima Fatty Rats. Cardiovasc Drugs Ther 28, 211–220 (2014). https://doi.org/10.1007/s10557-014-6519-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10557-014-6519-8

Keywords

Search

Navigation