title: Vessel wall, not platelet, P2Y12 potentiates early atherogenesis.
abstract: OBJECTIVE
  Platelets have a fundamental role in atherothrombosis, but their role in early atherogenesis is unclear. The P2Y12 receptor is responsible for amplifying and sustaining platelet activation and P2Y12 inhibition is crucial in modulating the vessel wall response to injury. We therefore examined the role of platelet vs. vessel wall P2Y12 in early atherogenesis and considered the use of P2Y12 antagonists ticagrelor and clopidogrel in modulating this process.
  
  
  RESULTS
  ApoE(-/-) and ApoE(-/-)P2Y12 (-/-) male mice underwent bone marrow transplantation and were fed a western diet for 4 weeks before assessing atherosclerotic burden. Compared with ApoE(-/-) controls, platelet P2Y12 deficiency profoundly reduced platelet reactivity but had no effect on atheroma formation, whereas vessel wall P2Y12 deficiency significantly attenuated atheroma in the aortic sinus and brachiocephalic artery (both P < 0.001). ApoE(-/-) and ApoE(-/-)P2Y12 (-/-) male mice fed western diet plus either twice-daily doses of ticagrelor (100 mg/kg) or daily clopidogrel (20 mg/kg) for 4 weeks exhibited no significant reduction in atheroma compared with control mice fed mannitol. Attenuated P-selectin expression confirmed platelet P2Y12 inhibition in drug-treated mice.
  
  
  CONCLUSIONS
  Despite its major contribution to platelet reactivity, platelet P2Y12 has no effect on early atheroma formation, whereas vessel wall P2Y12 is important in this process. Ticagrelor and clopidogrel effectively reduced platelet reactivity but were unable to inhibit early atherogenesis, demonstrating that these P2Y12 inhibitors may not be effective in preventing early disease.
authors: Department of Cardiovascular Science, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK.
authors: Laura E
authors: LE
authors: West
authors: Department of Cardiovascular Science, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK.
authors: Tanja
authors: T
authors: Steiner
authors: Department of Cardiovascular Science, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK.
authors: Heather M
authors: HM
authors: Judge
authors: Department of Cardiovascular Science, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK.
authors: Sheila E
authors: SE
authors: Francis
authors: Department of Cardiovascular Science, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK r.f.storey@sheffield.ac.uk.
authors: Robert F
authors: RF
authors: Storey
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology; D050197:Atherosclerosis / Q000209:etiology*; D001792:Blood Platelets / Q000502:physiology*; D001808:Blood Vessels / Q000502:physiology*; D000077144:Clopidogrel; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019007:P-Selectin / Q000502:physiology; D058925:Receptors, Purinergic P2Y12 / Q000502:physiology*; D000077486:Ticagrelor; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D001057:Apolipoproteins E; D019007:P-Selectin; C548577:P2ry12 protein, mouse; D058925:Receptors, Purinergic P2Y12; D000077144:Clopidogrel; D000077486:Ticagrelor; D000241:Adenosine; D013988:Ticlopidine
keywords: Atherogenesis; Clopidogrel; P2Y12; Platelet; Ticagrelor