Enhanced platelet reactivity and thrombosis in Apoe-/- mice exposed to cigarette smoke is attenuated by P2Y12 antagonism.
BACKGROUND
Smoking increases the risk of acute arterial thrombosis, including myocardial infarction, likely due to multi-factorial effects on the vasculature. Heightened platelet reactivity may be among the adverse effects of smoke exposure.


METHODS
To examine the effects of smoke exposure on platelet function in an atherosclerotic environment, Apoe-deficient female mice, maintained on a Western diet, were exposed (4 hrs/d, 5 d/wk) to sidestream cigarette smoke in a whole-body exposure chamber for 12 weeks. A separate group of wild type C57BL/6J mice were also exposed to smoke in an identical fashion.


RESULTS
In comparison to control Apoe-/- mice exposed to filtered ambient air, smoke-exposed Apoe-/- mice displayed a 1.8±0.3 fold enhanced ADP-induced fibrinogen binding ex vivo (P<0.001) and had a shorter time to thrombotic occlusion following ferric chloride injury of the carotid artery (median time to thrombosis of 8 vs. 13 min; P=0.015). Administration of the direct-acting P2Y12 antagonist cangrelor blunted ex vivo fibrinogen binding and attenuated thrombosis (median time 20 min) in Apoe-/- mice exposed to sidestream smoke. The effects of smoke exposure required a proatherosclerotic background, as wild-type C57Bl/6J mice exposed to smoke displayed similar fibrinogen binding and thrombotic occlusion times as did control mice.


CONCLUSIONS
Our results demonstrate that exposure to smoke heightens platelet reactivity and thrombosis in Apoe-/- mice and implicate signaling through platelet P2Y12 receptor as a mediator of the adverse consequence of smoke exposure. These results may partially explain the recent observations that smokers derive greater clinical benefit from the P2Y12 antagonist clopidogrel than do non-smokers.
Dong
Anping
A
VA Medical Center Lexington, Division of Cardiovascular Medicine, The Gill Heart Institute, University of Kentucky, USA. adong2@uky.edu
Caicedo
Jessica
J
Han
Sung Gu
SG
Mueller
Paul
P
Saha
Sibu
S
Smyth
Susan S
SS
Gairola
C Gary
CG
D000249:Adenosine Monophosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D001792:Blood Platelets / Q000378:metabolism*; D002712:Chlorides; D005260:Female; D005290:Ferric Compounds; D005340:Fibrinogen / Q000378:metabolism; D017353:Gene Deletion; D051379:Mice; D008810:Mice, Inbred C57BL; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology; D058925:Receptors, Purinergic P2Y12 / Q000378:metabolism*; D013927:Thrombosis / Q000139:chemically induced / Q000209:etiology*; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
D001057:Apolipoproteins E; D002712:Chlorides; D005290:Ferric Compounds; C548577:P2ry12 protein, mouse; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D014028:Tobacco Smoke Pollution; D000249:Adenosine Monophosphate; C117446:cangrelor; D005340:Fibrinogen; C024555:ferric chloride
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