Skip to main content

Advertisement

SpringerLink
Log in

Plasma Glycoproteomic Study of Therapeutic Hypothermia Reveals Novel Markers Predicting Neurologic Outcome Post-cardiac Arrest

  • Original Article
  • Published:
Translational Stroke Research Aims and scope Submit manuscript

Abstract

Therapeutic hypothermia (TH) is a neuroprotective treatment post-cardiac arrest but is grossly underutilized. After TH induction, traditional biomarkers and parameters can no long predict clinical outcome due to a lack of understanding of hypothermic response. Innovative approaches to better understand the clinical effect of TH will help to prognosticate outcome and expand beneficial population. Protein glycosylation is an important extracellular post-translational modification, regulating various extracellular signaling pathways. Here, we used glycoproteomics to investigate the association of plasma glycoproteins with the prognosis of TH-treated cardiac arrest patients. Using lectin affinity chromatography and mass spectrometry, we identified 640 glycoproteins in the plasma of cardiac arrest patients undergoing TH treatment, of which 23 were up-regulated and 14 were down-regulated in good outcome patients as compared with poor outcome ones. Notably, two glycoproteins with antioxidant activity, ceruloplasmin (CP) and haptoglobin (HP), were found to be associated with favorable neurologic outcome. This was further supported by ELISA assay in a large patients cohort, in which glycosylated CP and HP enriched by concanavilin A (ConA) and wheat germ agglutinin (WGA) lectins were significantly increased in patients developing good outcome (ConA-CP: p = 0.033; ConA-HP: p = 0.04; WGA-HP: p = 0.021). Furthermore, ROC analysis demonstrated the predictive potential of ConA-CP, ConA-HP, and WGA-HP (ConA-CP: AUC = 0.732, p = 0.031; ConA-HP: AUC = 0.746, p = 0.022; WGA-HP: AUC = 0.714, p = 0.046) and combination of them improved the predictive power (AUC = 0.830, p = 0.002). Our results suggested that glycosylated CP and HP as well as other glycoproteins may play critical roles in neuroprotection and serve as sensitive prognostic markers for TH treatments.

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

Similar content being viewed by others

References

  1. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346(8):557–63. doi:10.1056/NEJMoa003289.

    Article  PubMed  Google Scholar 

  2. Hypothermia after Cardiac Arrest Study G. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346(8):549–56. doi:10.1056/NEJMoa012689.

    Article  Google Scholar 

  3. Nolan JP, Morley PT, Vanden Hoek TL, Hickey RW, Kloeck WG, Billi J, et al. Therapeutic hypothermia after cardiac arrest: an advisory statement by the advanced life support task force of the International Liaison Committee on Resuscitation. Circulation. 2003;108(1):118–21. doi:10.1161/01.CIR.0000079019.02601.90.

    Article  CAS  PubMed  Google Scholar 

  4. Al Thenayan E, Savard M, Sharpe M, Norton L, Young B. Predictors of poor neurologic outcome after induced mild hypothermia following cardiac arrest. Neurology. 2008;71(19):1535–7. doi:10.1212/01.wnl.0000334205.81148.31.

    Article  PubMed  Google Scholar 

  5. Mortberg E, Zetterberg H, Nordmark J, Blennow K, Rosengren L, Rubertsson S. S-100B is superior to NSE, BDNF and GFAP in predicting outcome of resuscitation from cardiac arrest with hypothermia treatment. Resuscitation. 2011;82(1):26–31. doi:10.1016/j.resuscitation.2010.10.011.

    Article  PubMed  Google Scholar 

  6. Clerc F, Reiding KR, Jansen BC, Kammeijer GS, Bondt A, Wuhrer M. Human plasma protein N-glycosylation. Glycoconj J. 2016;33(3):309–43. doi:10.1007/s10719-015-9626-2.

    Article  CAS  PubMed  Google Scholar 

  7. Hansson K, Stenflo J. Post-translational modifications in proteins involved in blood coagulation. J Thromb Haemost. 2005;3(12):2633–48. doi:10.1111/j.1538-7836.2005.01478.x.

    Article  CAS  PubMed  Google Scholar 

  8. Maverakis E, Kim K, Shimoda M, Gershwin ME, Patel F, Wilken R, et al. Glycans in the immune system and the altered glycan theory of autoimmunity: a critical review. J Autoimmun. 2015;57:1–13. doi:10.1016/j.jaut.2014.12.002.

    Article  CAS  PubMed  Google Scholar 

  9. Sharon N. Lectins: past, present and future. Biochem Soc Trans. 2008;36(Pt 6):1457–60.

    Article  CAS  PubMed  Google Scholar 

  10. Butterfield DA, Owen JB. Lectin-affinity chromatography brain glycoproteomics and Alzheimer disease: insights into protein alterations consistent with the pathology and progression of this dementing disorder. Proteomics Clin Appl. 2011;5(1–2):50–6. doi:10.1002/prca.201000070.

    Article  CAS  PubMed  Google Scholar 

  11. Wang Y, Ao X, Vuong H, Konanur M, Miller FR, Goodison S, et al. Membrane glycoproteins associated with breast tumor cell progression identified by a lectin affinity approach. J Proteome Res. 2008;7(10):4313–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Deng WJ, Nie S, Dai J, Wu JR, Zeng R. Proteome, phosphoproteome, and hydroxyproteome of liver mitochondria in diabetic rats at early pathogenic stages. Mol Cell Proteomics. 2010;9(1):100–16. doi:10.1074/mcp.M900020-MCP200.

    Article  CAS  PubMed  Google Scholar 

  13. Pencina MJ, D'Agostino RB. Overall C as a measure of discrimination in survival analysis: model specific population value and confidence interval estimation. Stat Med. 2004;23(13):2109–23. doi:10.1002/sim.1802.

    Article  PubMed  Google Scholar 

  14. Huang da W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4(1):44–57. doi:10.1038/nprot.2008.211.

    Article  PubMed  Google Scholar 

  15. Burkitt MJ. A critical overview of the chemistry of copper-dependent low density lipoprotein oxidation: roles of lipid hydroperoxides, alpha-tocopherol, thiols, and ceruloplasmin. Arch Biochem Biophys. 2001;394(1):117–35. doi:10.1006/abbi.2001.2509.

    Article  CAS  PubMed  Google Scholar 

  16. Van Vlierberghe H, Langlois M, Delanghe J. Haptoglobin polymorphisms and iron homeostasis in health and in disease. Clin Chim Acta. 2004;345(1–2):35–42. doi:10.1016/j.cccn.2004.03.016.

    Article  PubMed  Google Scholar 

  17. Polderman KH. Mechanisms of action, physiological effects, and complications of hypothermia. Crit Care Med. 2009;37(7 Suppl):S186–202. doi:10.1097/CCM.0b013e3181aa5241.

    Article  PubMed  Google Scholar 

  18. Tang XN, Yenari MA. Hypothermia as a cytoprotective strategy in ischemic tissue injury. Ageing Res Rev. 2010;9(1):61–8.

    Article  PubMed  Google Scholar 

  19. Vosler PS, Logue ES, Repine MJ, Callaway CW. Delayed hypothermia preferentially increases expression of brain-derived neurotrophic factor exon III in rat hippocampus after asphyxial cardiac arrest. Brain Res Mol Brain Res. 2005;135(1–2):21–9. doi:10.1016/j.molbrainres.2004.11.006.

    Article  CAS  PubMed  Google Scholar 

  20. Rundgren M, Karlsson T, Nielsen N, Cronberg T, Johnsson P, Friberg H. Neuron specific enolase and S-100B as predictors of outcome after cardiac arrest and induced hypothermia. Resuscitation. 2009;80(7):784–9. doi:10.1016/j.resuscitation.2009.03.025.

    Article  CAS  PubMed  Google Scholar 

  21. Tiainen M, Roine RO, Pettila V, Takkunen O. Serum neuron-specific enolase and S-100B protein in cardiac arrest patients treated with hypothermia. Stroke. 2003;34(12):2881–6. doi:10.1161/01.STR.0000103320.90706.35.

    Article  CAS  PubMed  Google Scholar 

  22. Arumugam TV, Woodruff TM, Lathia JD, Selvaraj PK, Mattson MP, Taylor SM. Neuroprotection in stroke by complement inhibition and immunoglobulin therapy. Neuroscience. 2009;158(3):1074–89. doi:10.1016/j.neuroscience.2008.07.015.

    Article  CAS  PubMed  Google Scholar 

  23. Staikou C, Paraskeva A, Drakos E, Anastassopoulou I, Papaioannou E, Donta I, et al. Impact of graded hypothermia on coagulation and fibrinolysis. J Surg Res. 2011;167(1):125–30. doi:10.1016/j.jss.2009.07.037.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Clinical Proteomics Research Center and Cardio-Neurology Clinic, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, 175 Cambridge St, Suite 340, Boston, MA, 02114, USA

    Wenjun Deng, Jing Cao, Lei Chen, David McMullin, Ferdinando S. Buonanno, Eng H. Lo & MingMing Ning

  2. Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    James L. Januzzi Jr

  3. Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Eng H. Lo & MingMing Ning

Authors
  1. Wenjun Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jing Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lei Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David McMullin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. James L. Januzzi Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ferdinando S. Buonanno
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eng H. Lo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. MingMing Ning
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to MingMing Ning.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

Funding

This study was funded by the U.S. National Institutes of Health: NS051588 (M.N.) and NS052498 (M.N., E.H.L).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Deng, W., Cao, J., Chen, L. et al. Plasma Glycoproteomic Study of Therapeutic Hypothermia Reveals Novel Markers Predicting Neurologic Outcome Post-cardiac Arrest. Transl. Stroke Res. 9, 64–73 (2018). https://doi.org/10.1007/s12975-017-0558-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12975-017-0558-y

Keywords

Search

Navigation