Skip to main content

Advertisement

SpringerLink
Log in

Combination of necroptosis and apoptosis inhibition enhances cardioprotection against myocardial ischemia–reperfusion injury

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

Abstract

Purpose

Necroptosis has been proposed as a mode of cell death that is a caspase-independent programmed necrosis. We investigated whether necroptosis is involved in myocardial ischemia–reperfusion injury in isolated guinea pig hearts and, if so, whether simultaneous inhibition of necroptosis and apoptosis confers enhanced cardioprotection.

Methods

Isolated perfused guinea pig hearts were subjected to 30 min ischemia and 4 h reperfusion (control = CTL, n = 8). Necrostatin-1 (necroptosis inhibitor, 10 μM), Z-VAD (apoptosis inhibitor, 0.1 μM) and both inhibitors were administered starting 5 min before ischemia and during the initial 30 min of reperfusion (Nec, Z-VAD, Nec + Z-VAD; n = 8 each). Contractile recovery was monitored by left ventricular developed (LVDP) and end-diastolic (LVEDP) pressure. Infarct size was determined by triphenyltetrazolium chloride staining. Tissue samples were obtained after 4 h reperfusion to determine expression of receptor-interacting protein 1 (RIP1) and activated caspase 3 by Western blot analysis.

Results

After reperfusion, Nec + Z-VAD had higher LVDP and lower LVEDP compared with CTL. Infarct size was reduced in Nec and Z-VAD compared with CTL. Combination of necroptosis and apoptosis inhibition further reduced infarct size. Expression of activated caspase 3 was not increased in Z-VAD and Nec + Z-VAD compared with Nec and CTL. Expression of RIP1 was preserved in Z-VAD and Nec + Z-VAD compared with CTL, suggesting RIP1-mediated necrosis is involved in myocardial ischemia–reperfusion injury.

Conclusion

Necroptosis is involved in myocardial ischemia–reperfusion injury, and simultaneous inhibition of necroptosis and apoptosis enhances the cardioprotective effect. These findings may provide a novel, additive strategy for cardioprotection in acute myocardial infarction.

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. Gottlieb RA, Engler RL. Apoptosis in myocardial ischemia-reperfusion. Ann N Y Acad Sci. 1999;874:412–26.

    Article  PubMed  CAS  Google Scholar 

  2. Inamura Y, Miyamae M, Sugioka S, Domae N, Kotani J. Sevoflurane postconditioning prevents activation of caspase 3 and 9 through antiapoptotic signaling after myocardial ischemia-reperfusion. J Anesth. 2010;24:215–24.

    Article  PubMed  Google Scholar 

  3. Qiao S, Xie H, Wang C, Wu X, Liu H, Liu C. Delayed anesthetic preconditioning protects against myocardial infarction via activation of nuclear factor-κB and upregulation of autophagy. J Anesth. 2013;27:251–60.

    Article  PubMed  Google Scholar 

  4. Smith CA, Williams GT, Kingston R, Jenkinson EJ, Owen JJ. Apoptosis. Nature (Lond) 1989;338:10.

    Google Scholar 

  5. Kitanaka C, Kuchino Y. Caspase-independent programmed cell death with necrotic morphology. Cell Death Differ. 1999;6:508–15.

    Article  PubMed  CAS  Google Scholar 

  6. Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N, Cuny GD, Mitchison TJ, Moskowitz MA, Yuan J. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol. 2005;1:112–9.

    Article  PubMed  CAS  Google Scholar 

  7. Declercq W, Vanden Berghe T, Vandenabeele P. RIP kinases at the crossroads of cell death and survival. Cell. 2009;138:229–32.

    Article  PubMed  CAS  Google Scholar 

  8. Christofferson DE, Li Y, Hitomi J, Zhou W, Upperman C, Zhu H, Gerber SA, Gygi S, Yuan J. A novel role for RIP1 kinase in mediating TNFα production. Cell Death Dis. 2012;3:e320.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  9. Degterev A, Hitomi J, Germscheid M, Ch’en IL, Korkina O, Teng X, Abbott D, Cuny GD, Yuan C, Wagner G, Hedrick SM, Gerber SA, Lugovskoy A, Yuan J. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol. 2008;4:313–21.

    Article  PubMed  CAS  Google Scholar 

  10. Smith CC, Davidson SM, Lim SY, Simpkin JC, Hothersall JS, Yellon DM. Necrostatin: a potentially novel cardioprotective agent? Cardiovasc Drugs Ther. 2007;21:227–33.

    Article  PubMed  CAS  Google Scholar 

  11. Wang YQ, Wang L, Zhang MY, Wang T, Bao HJ, Liu WL, Dai DK, Zhang L, Chang P, Dong WW, Chen XP, Tao LY. Necrostatin-1 suppresses autophagy and apoptosis in mice traumatic brain injury model. Neurochem Res. 2012;37:1849–58.

    Article  PubMed  CAS  Google Scholar 

  12. Fishbein MC, Meerbaum S, Rit J, Lando U, Kanmatsuse K, Mercier JC, Corday E, Ganz W. Early phase acute myocardial infarct size quantification: validation of the triphenyl tetrazolium chloride tissue enzyme staining technique. Am Heart J. 1981;101:593–600.

    Article  PubMed  CAS  Google Scholar 

  13. Dorn GW 2nd. Apoptotic and non-apoptotic programmed cardiomyocyte death in ventricular remodelling. Cardiovasc Res. 2009;81:465–73.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  14. Yaoita H, Ogawa K, Maehara K, Maruyama Y. Attenuation of ischemia/reperfusion injury in rats by a caspase inhibitor. Circulation. 1998;97:276–81.

    Article  PubMed  CAS  Google Scholar 

  15. Holler N, Zaru R, Micheau O, Thome M, Attinger A, Valitutti S, Bodmer JL, Schneider P, Seed B, Tschopp J. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol. 2000;1:489–95.

    Article  PubMed  CAS  Google Scholar 

  16. Liu J, van Mil A, Vrijsen K, Zhao J, Gao L, Metz CH, Goumans MJ, Doevendans PA, Sluijter JP. MicroRNA-155 prevents necrotic cell death in human cardiomyocyte progenitor cells via targeting RIP1. J Cell Mol Med. 2010;15:1474–82.

    Article  PubMed  CAS  Google Scholar 

  17. Lim SY, Davidson SM, Mocanu MM, Yellon DM, Smith CC. The cardioprotective effect of necrostatin requires the cyclophilin-D component of the mitochondrial permeability transition pore. Cardiovasc Drugs Ther. 2007;21:467–9.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  18. Garlid KD, Costa AD, Quinlan CL, Pierre SV, Dos Santos P. Cardioprotective signaling to mitochondria. J Mol Cell Cardiol. 2009;46:858–66.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  19. Chavez-Valdez R, Martin LJ, Flock DL, Northington FJ. Necrostatin-1 attenuates mitochondrial dysfunction in neurons and astrocytes following neonatal hypoxia–ischemia. Neuroscience. 2012;219:192–203.

    Article  PubMed  CAS  Google Scholar 

  20. Laukens B, Jennewein C, Schenk B, Vanlangenakker N, Schier A, Cristofanon S, Zobel K, Deshayes K, Vucic D, Jeremias I, Bertrand MJ, Vandenabeele P, Fulda S. Smac mimetic bypasses apoptosis resistance in FADD- or caspase-8-deficient cells by priming for tumor necrosis factor alpha-induced necroptosis. Neoplasia. 2011;13:971–9.

    PubMed Central  PubMed  CAS  Google Scholar 

  21. Mocanu MM, Baxter GF, Yellon DM. Caspase inhibition and limitation of myocardial infarct size: protection against lethal reperfusion injury. Br J Pharmacol. 2000;130:197–200.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  22. Schwarz ER, Somoano Y, Hale SL, Kloner RA. What is the required reperfusion period for assessment of myocardial infarct size using triphenyltetrazolium chloride staining in the rat? J Thromb Thrombolysis. 2000;10:181–7.

    Article  PubMed  CAS  Google Scholar 

  23. Kajstura J, Cheng W, Reiss K, Clark WA, Sonnenblick EH, Krajewski S, Reed JC, Olivetti G, Anversa P. Apoptotic and necrotic myocyte cell deaths are independent contributing variables of infarct size in rats. Lab Invest. 1996;74:86–107.

    PubMed  CAS  Google Scholar 

  24. Scarabelli T, Stephanou A, Rayment N, Pasini E, Comini L, Curello S, Ferrari R, Knight R, Latchman D. Apoptosis of endothelial cells precedes myocyte cell apoptosis in ischemia/reperfusion injury. Circulation. 2001;104:253–6.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Dr. Hirofumi Sawai for excellent advice. This study was supported by Osaka Dental University (Osaka, Japan) Research Funds (12-13) (Shizuka Koshinuma) and Grant-in-Aid for Scientific Research (C) 23593008 from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Masami Miyamae) (Tokyo, Japan).

Conflict of interest

The authors have no conflicts of interest to report.

Author information

Authors and Affiliations

  1. Department of Anesthesiology, Graduate School of Dentistry, Osaka Dental University, Osaka, Japan

    Shizuka Koshinuma

  2. Department of Internal Medicine, Osaka Dental University, 8-1 Kuzuha Hanazono-cho, Hirakata, Osaka, 573-1121, Japan

    Masami Miyamae

  3. Department of Anesthesiology, Osaka Dental University, Osaka, Japan

    Kazuhiro Kaneda & Junichiro Kotani

  4. Institute for Heart and Vascular Health, Einstein Medical Center, Jefferson Medical College, Philadelphia, USA

    Vincent M. Figueredo

Authors
  1. Shizuka Koshinuma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masami Miyamae
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kazuhiro Kaneda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Junichiro Kotani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Vincent M. Figueredo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Masami Miyamae.

About this article

Cite this article

Koshinuma, S., Miyamae, M., Kaneda, K. et al. Combination of necroptosis and apoptosis inhibition enhances cardioprotection against myocardial ischemia–reperfusion injury. J Anesth 28, 235–241 (2014). https://doi.org/10.1007/s00540-013-1716-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00540-013-1716-3

Keywords

Search

Navigation