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Cangrelor-Mediated Cardioprotection Requires Platelets and Sphingosine Phosphorylation

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Abstract

In animal models platelet P2Y12 receptor antagonists put the heart into a protected state, not as a result of suppressed thrombosis but rather through protective signaling, similar to that for ischemic postconditioning. While both ischemic postconditioning and the P2Y12 blocker cangrelor protect blood-perfused hearts, only the former protects buffer-perfused hearts indicating that the blocker requires a blood-borne constituent or factor to protect. We used an anti-platelet antibody to make thrombocytopenic rats to test if that factor resides within the platelet. Infarct size was measured in open-chest rats subjected to 30-min ischemia/2-h reperfusion. Infarct size was not different in thrombocytopenic rats showing that preventing aggregation alone is not protective. While ischemic preconditioning could reduce infarct size in thrombocytopenic rats, the P2Y12 inhibitor cangrelor could not, indicating that it protects by interacting with some factor in the platelet. Ischemic preconditioning is known to require phosphorylation of sphingosine. In rats treated with dimethylsphingosine to block sphingosine kinase, cangrelor was no longer protective. Thus cangrelor’s protective mechanism appears to also involve sphingosine kinase revealing yet another similarity to conditioning’s mechanism.

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References

  1. Yang X-M, Liu Y, Cui L, Yang X, Liu Y, Tandon N, et al. Platelet P2Y12 blockers confer direct postconditioning-like protection in reperfused rabbit hearts. J Cardiovasc Pharmacol Ther. 2013;18:251–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Yang X-M, Cui L, Alhammouri A, Downey JM, Cohen MV. Triple therapy greatly increases myocardial salvage during ischemia/reperfusion in the in situ rat heart. Cardiovasc Drugs Ther. 2013;27:403–12.

    Article  CAS  PubMed  Google Scholar 

  3. Bell RM, Sivaraman V, Kunuthur SP, Cohen MV, Downey JM, Yellon DM. Cardioprotective properties of the platelet P2Y12 receptor inhibitor, cangrelor: protective in diabetics and reliant upon the presence of blood. Cardiovasc Drugs Ther 2015;29:415–8.

  4. Jin Z-Q, Goetzl EJ, Karliner JS. Sphingosine kinase activation mediates ischemic preconditioning in murine heart. Circulation. 2004;110:1980–9.

    Article  CAS  PubMed  Google Scholar 

  5. Lecour S, Smith RM, Woodward B, Opie LH, Rochette L, Sack MN. Identification of a novel role for sphingolipid signaling in TNFα and ischemic preconditioning mediated cardioprotection. J Mol Cell Cardiol. 2002;34:509–18.

    Article  CAS  PubMed  Google Scholar 

  6. Knapp M Cardioprotective role of sphingosine-1-phosphate. J Physiol Pharmacol. 2011;62:601–7.

    CAS  PubMed  Google Scholar 

  7. Somers SJ, Frias M, Lacerda L, Opie LH, Lecour S. Interplay between SAFE and RISK pathways in sphingosine-1-phosphate-induced cardioprotection. Cardiovasc Drugs Ther. 2012;26:227–37.

    Article  CAS  PubMed  Google Scholar 

  8. National Research Council. Guide for the Care and Use of Laboratory Animals. 7th ed. Washington, D.C.:National Academy Press;1996.

  9. Hausenloy DJ, Duchen MR, Yellon DM. Inhibiting mitochondrial permeability transition pore opening at reperfusion protects against ischaemia-reperfusion injury. Cardiovasc Res. 2003;60:617–25.

    Article  CAS  PubMed  Google Scholar 

  10. Sandhu R, Diaz RJ, Wilson GJ. Comparison of ischaemic preconditioning in blood perfused and buffer perfused isolated heart models. Cardiovasc Res. 1993;27:602–7.

    Article  CAS  PubMed  Google Scholar 

  11. Yang X-M, Philipp S, Downey JM, Cohen MV. Postconditioning's protection is not dependent on circulating blood factors or cells but involves adenosine receptors and requires PI3-kinase and guanylyl cyclase activation. Basic Res Cardiol. 2005;100:57–63.

    Article  CAS  PubMed  Google Scholar 

  12. Tani M, Sano T, Ito M, Igarashi Y. Mechanisms of sphingosine and sphingosine 1-phosphate generation in human platelets. J Lipid Res. 2005;46:2458–67.

    Article  CAS  PubMed  Google Scholar 

  13. Hausenloy DJ, Yellon DM. New directions for protecting the heart against ischaemia-reperfusion injury: targeting the Reperfusion Injury Salvage Kinase (RISK)-pathway. Cardiovasc Res. 2004;61:448–60.

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Authors and Affiliations

  1. Department of Physiology and Cell Biology, College of Medicine, University of South Alabama, Mobile, AL, USA

    Michael V. Cohen, Xi-Ming Yang, James White & James M. Downey

  2. Department of Medicine, College of Medicine, University of South Alabama, Mobile, AL, USA

    Michael V. Cohen

  3. Hatter Cardiovascular Institute, London, UK

    Derek M. Yellon & Robert M. Bell

  4. Institute for Cardiovascular Science, University College London, London, UK

    Derek M. Yellon & Robert M. Bell

Authors
  1. Michael V. Cohen
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  2. Xi-Ming Yang
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  3. James White
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  4. Derek M. Yellon
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  5. Robert M. Bell
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  6. James M. Downey
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Corresponding author

Correspondence to Michael V. Cohen.

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These studies were funded in part by an unrestricted grant from The Medicines Company, Parsippany, NJ. Cangrelor was a gift from The Medicines Company.

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Cohen, M.V., Yang, XM., White, J. et al. Cangrelor-Mediated Cardioprotection Requires Platelets and Sphingosine Phosphorylation. Cardiovasc Drugs Ther 30, 229–232 (2016). https://doi.org/10.1007/s10557-015-6633-2

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  • DOI: https://doi.org/10.1007/s10557-015-6633-2

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