Skip to main content
SpringerLink
Log in

Chronic type-I diabetes could not impede the anti-inflammatory and anti-apoptotic effects of combined postconditioning with ischemia and cyclosporine A in myocardial reperfusion injury

  • Original Article
  • Published:
Journal of Physiology and Biochemistry Aims and scope Submit manuscript

Abstract

It has been shown that diabetes modifies the myocardial responses to ischemia/reperfusion (I/R) and to cardioprotective agents. In this study, we aimed to investigate the effects of combined treatment with ischemic postconditioning (IPostC) and cyclosporine A (CsA) on inflammation and apoptosis of the diabetic myocardium injured by I/R. Eight weeks after induction of diabetes in Wistar rats, hearts were mounted on a Langendorff apparatus and were subsequently subjected to a 30-min regional ischemia followed by 45-min reperfusion. IPostC was induced at the onset of reperfusion, by 3 cycles of 30-s reperfusion/ischemia (R/I). The concentration of creatine kinase (CK), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 were determined; the levels of total and phosphorylated glycogen synthase kinase 3 beta (p-GSK3β) and B-cell lymphoma 2 (Bcl-2) were quantified by western blotting, and the rate of apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. Administration of either IPostC or CsA alone in nondiabetic animals significantly reduced CK, TNF-α, IL-1β, and IL-6 concentrations, increased the p-GSK3β and Bcl-2, and decreased the level of apoptosis (P < 0.05) but had no effect on diabetic hearts. However, in diabetic animals, after administration of CsA, the cardioprotective effects of IPostC in increasing the p-GSK3β and Bcl-2 and decreasing apoptosis and inflammation were restored in comparison with nonpostconditioned diabetic hearts. IPostC or CsA failed to affect apoptosis and inflammation and failed to protect the diabetic myocardium against I/R injury. However, combined administration of IPostC and CsA at reperfusion can protect the diabetic myocardium by decreasing the inflammatory response and apoptosis.

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
Fig. 5

Similar content being viewed by others

Abbreviations

CsA:

Cyclosporine-A

I/R:

Ischemia/reperfusion

IPostC:

Ischemic postconditioning

ERK:

Extracellular signal-regulated kinase

MEK:

Mitogene-activated protein kinase/ERK kinase

PI3K/Akt:

Phosphoinositide-3-kinase/protein kinase B

PKC:

Protein kinase C

mPTP:

Mitochondrial permeability transition pore

GSK3β:

Glycogen synthase kinase-3 beta

TNF-α:

Tumor necrosis factor-α

IL-:

Interleukin-

CK:

Creatine kinase

References

  1. Argaud L, Gateau-Roesch O, Chalabreysse L, Gomez L, Loufouat J, Thivolet-Béjui F, Robert D, Ovize M (2004) Preconditioning delays Ca2+-induced mitochondrial permeability transition. Cardiovas Res 61:115–122

    Article  CAS  Google Scholar 

  2. Argaud L, Gateau-Roesch O, Raisky O, Loufouat J, Robert D, Ovize M (2005) Postconditioning inhibits mitochondrial permeability transition. Circulation 111:194–197

    Article  CAS  PubMed  Google Scholar 

  3. Badalzadeh R, Mohammadi M, Najafi M, Ahmadiasl N, Farajnia S, Ebrahimi H (2012) The additive effects of ischemic postconditioning and cyclosporine-A on nitric oxide activity and functions of diabetic myocardium injured by ischemia/reperfusion. J Cardiovasc Pharmacol Ther 17:181–189

    Article  CAS  PubMed  Google Scholar 

  4. Badalzadeh R, Yousefi B, Majidinia M, Ebrahimi H (2014a) Anti-arrhythmic effect of diosgenin in reperfusion-induced myocardial injury in a rat model: activation of nitric oxide system and mitochondrial KATP channel. J Physiol Sci 64:393–400

    Article  CAS  PubMed  Google Scholar 

  5. Badalzadeh R, Yousefi B, Tajaddini A, Ahmadian N (2014b) Diosgenin-induced protection against myocardial ischaemia-reperfusion injury is mediated by mitochondrial KATP channels in a rat model. Perfusion 0267659114566064.

  6. Badalzadeh R, Mokhtari B, Yavari R (2015a) Contribution of apoptosis in myocardial reperfusion injury and loss of cardioprotection in diabetes mellitus. J Physiol Sci 65:201–215

    Article  PubMed  Google Scholar 

  7. Badalzadeh R, Mohammadi M, Yousefi B, Faranjia S, Najafi M, Mohammadi S (2015b) Involvement of glycogen synthase kinase-3β and oxidation status in the loss of cardioprotection by postconditioning in chronic diabetic male rats. Adv Pharm Bull 5(3):321–327

  8. Bopassa J-C, Ferrera R, Gateau-Roesch O, Couture-Lepetit E, Ovize M (2006) PI 3-kinase regulates the mitochondrial transition pore in controlled reperfusion and postconditioning. Cardiovasc Res 69:178–185

    Article  CAS  PubMed  Google Scholar 

  9. Drenger B, Ostrovsky IA, Barak M, Nechemia-Arbely Y, Ziv E, Axelrod JH (2011) Diabetes blockade of sevoflurane postconditioning is not restored by insulin in the rat heart: phosphorylated signal transducer and activator of transcription 3–and phosphatidylinositol 3-kinase–mediated inhibition. Anesthesiology 114:1364–1372

    Article  CAS  PubMed  Google Scholar 

  10. Ebrahimi H, Badalzadeh R, Mohammadi M, Yousefi B (2014) Diosgenin attenuates inflammatory response induced by myocardial reperfusion injury: role of mitochondrial ATP-sensitive potassium channels. J Physiol Biochem 70:425–432

    Article  CAS  PubMed  Google Scholar 

  11. Freude B, Masters TN, Robicsek F, Fokin A, Kostin S, Zimmermann R, Ullmann C, Lorenz-Meyer S, Schaper J (2000) Apoptosis is initiated by myocardial ischemia and executed during reperfusion. J Mol Cell Cardiol 32:197–208

    Article  CAS  PubMed  Google Scholar 

  12. Gottlieb RA, Burleson K, Kloner RA, Babior B, Engler R (1994) Reperfusion injury induces apoptosis in rabbit cardiomyocytes. J Clin Invest 94:1621

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hausenloy DJ (2009) Signalling pathways in ischaemic postconditioning. Thromb Haemost 101:626–634

    CAS  PubMed  Google Scholar 

  14. Huhn R, Heinen A, Hollmann MW, Schlack W, Preckel B, Weber NC (2010) Cyclosporine A administered during reperfusion fails to restore cardioprotection in prediabetic Zucker obese rats in vivo. Nutr Metab Cardiovasc Dis 20:706–712

    Article  CAS  PubMed  Google Scholar 

  15. Karimian A, Ahmadi Y, Yousefi B (2016) Multiple functions of p21 in cell cycle, apoptosis and transcriptional regulation after DNA damage. DNA repair 42:63–71

    Article  CAS  PubMed  Google Scholar 

  16. Kin H, Zhao Z-Q, Sun H-Y, Wang N-P, Corvera JS, Halkos ME, Kerendi F, Guyton RA, Vinten-Johansen J (2004) Postconditioning attenuates myocardial ischemia–reperfusion injury by inhibiting events in the early minutes of reperfusion. Cardiovasc Res 62:74–85

    Article  CAS  PubMed  Google Scholar 

  17. Kupai K, Csonka C, Fekete V, Odendaal L, Van Rooyen J, Csont T, Ferdinandy P (2009) Cholesterol diet-induced hyperlipidemia impairs the cardioprotective effect of postconditioning: role of peroxynitrite. Am J Physiol Heart Circ Physiol 297:1729–1735

    Article  Google Scholar 

  18. Miki T, Itoh T, Sunaga D, Miura T (2012) Effects of diabetes on myocardial infarct size and cardioprotection by preconditioning and postconditioning. Cardiovasc Diabetol 11:67

    Article  PubMed  PubMed Central  Google Scholar 

  19. Murphy E, Steenbergen C (2008) Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury. Physiol reviews 88:581–609

    Article  CAS  Google Scholar 

  20. Ovize M, Baxter GF, Di Lisa F, Ferdinandy P, Garcia-Dorado D, Hausenloy DJ, Heusch G, Vinten-Johansen J, Yellon DM, Schulz R (2010) Postconditioning and protection from reperfusion injury: where do we stand? Position paper from the working group of cellular biology of the Heart of the European Society of Cardiology. Cardiovasc Res 87:406–423

    Article  CAS  PubMed  Google Scholar 

  21. Przyklenk K, Maynard M, Greiner DL, Whittaker P (2011) Cardioprotection with postconditioning: loss of efficacy in murine models of type-2 and type-1 diabetes. Antioxid Redox Signal 14:781–790

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Rafiee P, Heidemann J, Ogawa H, Johnson N, Fisher PJ, Li M et al (2004) Cyclosporin A differentially inhibits multiple steps in VEGF induced angiogenesis in human microvascular endothelial cells through altered intracellular signaling. Cell Commun Signal 2:3

    Article  PubMed  PubMed Central  Google Scholar 

  23. Ren J-Y, Song J-X, Lu M-Y, Chen H (2011) Cardioprotection by ischemic postconditioning is lost in isolated perfused heart from diabetic rats: involvement of transient receptor potential vanilloid 1, calcitonin gene-related peptide and substance P. Regul Pept 169:49–57

    Article  CAS  PubMed  Google Scholar 

  24. Schwartz LM, Lagranha CJ (2006) Ischemic postconditioning during reperfusion activates Akt and ERK without protecting against lethal myocardial ischemia-reperfusion injury in pigs. Am J Physiol Heart Circ Physiol 290:1011–1018

    Article  Google Scholar 

  25. Song J-X, Wang L-H, Yao L, Xu C, Wei Z-H, Zheng L-R (2009) Impaired transient receptor potential vanilloid 1 in streptozotocin-induced diabetic hearts. Int J Cardiol 134:290–292

    Article  PubMed  Google Scholar 

  26. Wang SC, Tang CL, Piao HL, Zhu R, Sun C, Tao Y, Fu Q, Li DJ, Du MR (2013) Cyclosporine A promotes in vitro migration of human first-trimester trophoblasts via MAPK/ERK1/2-mediated NF-κB and Ca2+/calcineurin/NFAT signaling. Placenta 34(4):374–380

    Article  CAS  PubMed  Google Scholar 

  27. Yousefi B, Samadi N, Ahmadi Y (2014) Akt and p53R2, partners that dictate the progression and invasiveness of cancer. DNA repair 22:24–29

    Article  CAS  PubMed  Google Scholar 

  28. Zhao Z-Q, Vinten-Johansen J (2006) Postconditioning: reduction of reperfusion-induced injury. Cardiovasc Res 70:200–211

    Article  CAS  PubMed  Google Scholar 

  29. Zhao Z-Q, Corvera JS, Halkos ME, Kerendi F, Wang N-P, Guyton RA, Vinten-Johansen J (2003) Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol 54:579–588

    Article  Google Scholar 

  30. Zhao Z, Sun H, Wang N, Kin H, Guyton R, Vinten-Johansen J (2005) Hypoxic postconditioning attenuates cardiomyocyte apoptosis via inhibition of jnk and p38 kinases pathway. J Mol Cell Cardiol 38:870–870

    Google Scholar 

  31. Zheng L-R, Han J, Yao L, Sun Y-L, Jiang D-M, Hu S-J, Shao L, Sun Z-H, Wang L-H (2012) Up-regulation of calcitonin gene-related peptide protects streptozotocin-induced diabetic hearts from ischemia/reperfusion injury. Int J Cardiol 156:192–198

    Article  PubMed  Google Scholar 

  32. Zorov DB, Juhaszova M, Yaniv Y, Nuss HB, Wang S, Sollott SJ (2009) Regulation and pharmacology of the mitochondrial permeability transition pore. Cardiovasc Res 83:213–225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Reza Badalzadeh

  2. Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Reza Badalzadeh & Bahman Yousefi

  3. Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Reza Badalzadeh & Alireza Alihemmati

  4. Department of Basic Sciences, Maragheh University of Medical Sciences, Maragheh, Iran

    Ako Azimi

  5. Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

    Bahman Yousefi

Authors
  1. Reza Badalzadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ako Azimi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alireza Alihemmati
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bahman Yousefi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bahman Yousefi.

Ethics declarations

All animals received humane treatment in accordance with the regulation of the Care and Use of Laboratory Animals (National Institute of Health, publication no. 85–23, revised 1996). The experimental procedures were approved by the animal ethics committee of the Tabriz University of Medical Sciences (ethics approval number: A473/1–11-2013).

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Badalzadeh, R., Azimi, A., Alihemmati, A. et al. Chronic type-I diabetes could not impede the anti-inflammatory and anti-apoptotic effects of combined postconditioning with ischemia and cyclosporine A in myocardial reperfusion injury. J Physiol Biochem 73, 111–120 (2017). https://doi.org/10.1007/s13105-016-0530-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13105-016-0530-4

Keywords

Search

Navigation