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Cangrelor-Mediated Cardioprotection Requires Platelets and Sphingosine Phosphorylation

Michael V Cohen1,2, Xi-Ming Yang3, James White3

  • 1Department of Physiology and Cell Biology, College of Medicine, University of South Alabama, Mobile, AL, USA. mcohen@southalabama.edu.

Cardiovascular Drugs and Therapy
|January 20, 2016
PubMed

Insights

Platelet P2Y12 receptor antagonists protect the heart via signaling, not just by preventing clots. This protection requires a blood factor, likely within platelets, and involves sphingosine kinase, similar to ischemic preconditioning.

Area of Science:

  • Cardiovascular Research
  • Pharmacology
  • Cell Signaling

Background:

  • Platelet P2Y12 receptor antagonists offer cardioprotection in animal models through signaling pathways.
  • This protective effect differs from ischemic postconditioning, requiring blood-borne factors for P2Y12 blockers.
  • The role of platelets in mediating this protection is not fully understood.

Purpose of the Study:

  • To investigate the mechanism of cardioprotection by P2Y12 receptor antagonists.
  • To determine if platelets are essential for the protective effects of P2Y12 blockers.
  • To explore the relationship between P2Y12 inhibition, platelet factors, and sphingosine kinase signaling.

Main Methods:

  • Utilized thrombocytopenic rats induced by anti-platelet antibodies.
  • Measured infarct size in open-chest rats undergoing ischemia/reperfusion.
  • Administered P2Y12 inhibitor cangrelor and sphingosine kinase inhibitor dimethylsphingosine.

Main Results:

  • Thrombocytopenia did not affect infarct size, indicating platelet aggregation inhibition alone is insufficient for protection.
  • Cangrelor failed to protect thrombocytopenic rats, suggesting a platelet-dependent mechanism.
  • Blocking sphingosine kinase abolished cangrelor's protective effect, linking it to conditioning pathways.

Conclusions:

  • P2Y12 receptor antagonist-mediated cardioprotection relies on platelet-derived factors.
  • The protective mechanism involves sphingosine kinase, mirroring pathways of ischemic preconditioning.
  • Cangrelor's cardioprotective signaling is dependent on platelet interaction and sphingosine kinase activity.

Keywords:
CardioprotectionConditioningPlateletSphingosineSphingosine-1-phosphate

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