title: Cangrelor-Mediated Cardioprotection Requires Platelets and Sphingosine Phosphorylation.
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.
authors.affiliation: Department of Physiology and Cell Biology, College of Medicine, University of South Alabama, Mobile, AL, USA. mcohen@southalabama.edu.|Department of Medicine, College of Medicine, University of South Alabama, Mobile, AL, USA. mcohen@southalabama.edu.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Cohen
authors.affiliation: Department of Physiology and Cell Biology, College of Medicine, University of South Alabama, Mobile, AL, USA.
authors.forename: Xi-Ming
authors.initials: XM
authors.lastname: Yang
authors.affiliation: Department of Physiology and Cell Biology, College of Medicine, University of South Alabama, Mobile, AL, USA.
authors.forename: James
authors.initials: J
authors.lastname: White
authors.affiliation: Hatter Cardiovascular Institute, London, UK.|Institute for Cardiovascular Science, University College London, London, UK.
authors.forename: Derek M
authors.initials: DM
authors.lastname: Yellon
authors.affiliation: Hatter Cardiovascular Institute, London, UK.|Institute for Cardiovascular Science, University College London, London, UK.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Bell
authors.affiliation: Department of Physiology and Cell Biology, College of Medicine, University of South Alabama, Mobile, AL, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Downey
mesh_terms: D000249:Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects; D057775:Ischemic Postconditioning / Q000379:methods; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology*; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013110:Sphingosine / Q000378:metabolism*; D000099157:Sphingosine Kinase
chemical_list: D000249:Adenosine Monophosphate; D002316:Cardiotonic Agents; D017853:Phosphotransferases (Alcohol Group Acceptor); D020011:Protective Agents; D058921:Purinergic P2Y Receptor Antagonists; D013110:Sphingosine; D000099157:Sphingosine Kinase; C117446:cangrelor
keywords: Cardioprotection; Conditioning; Platelet; Sphingosine; Sphingosine-1-phosphate