Cangrelor-Mediated Cardioprotection Requires Platelets and Sphingosine Phosphorylation

Cardiovascular Drugs and Therapy
Michael V CohenJames M Downey

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 revea...Continue Reading

References

Jun 12, 2002·Journal of Molecular and Cellular Cardiology·Sandrine LecourMichael N Sack
Sep 29, 2004·Circulation·Zhu-Qiu JinJoel S Karliner
Aug 3, 2005·Journal of Lipid Research·Motohiro TaniYasuyuki Igarashi
Mar 7, 2012·Cardiovascular Drugs and Therapy·Sarin J SomersSandrine Lecour
Dec 13, 2012·Journal of Cardiovascular Pharmacology and Therapeutics·Xi-Ming YangMichael V Cohen
Jul 9, 2013·Cardiovascular Drugs and Therapy·Xi-Ming YangMichael V Cohen

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Citations

Aug 16, 2016·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Zoubir DjeradaHervé Millart
Apr 7, 2017·Journal of Cardiovascular Pharmacology and Therapeutics·Michael Rahbek SchmidtHans Erik Bøtker
Aug 11, 2017·Journal of Cardiovascular Pharmacology and Therapeutics·Karin Przyklenk, Peter Whittaker
Nov 14, 2018·Clinical Cardiology·Heerajnarain BulluckDerek J Hausenloy
Jan 19, 2018·Basic Research in Cardiology·David KöhlerPeter Rosenberger
Dec 28, 2018·Cardiovascular Research·Sean M DavidsonPéter Ferdinandy
Feb 13, 2019·Journal of Cardiovascular Pharmacology and Therapeutics·Xi-Ming YangMichael V Cohen
Mar 25, 2019·Cardiovascular Research·Melanie ZieglerKarlheinz Peter
Jul 10, 2019·Journal of Cardiovascular Pharmacology and Therapeutics·Eduardo FuentesAndres Trostchansky
Oct 28, 2019·Journal of Cardiovascular Pharmacology and Therapeutics·Michael V Cohen, James M Downey
Jun 2, 2017·Cardiovascular Diabetology·Isabella RussoPasquale Pagliaro
Jun 15, 2021·Cardiology Research and Practice·Kornela HałuchaIwona Bil-Lula

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