Title | Enhanced platelet reactivity and thrombosis in Apoe-/- mice exposed to cigarette smoke is attenuated by P2Y12 antagonism. |
Publication Type | Journal Article |
Year of Publication | 2010 |
Authors | Dong A, Caicedo J, Han SGu, Mueller P, Saha S, Smyth SS, C Gairola G |
Journal | Thromb Res |
Volume | 126 |
Issue | 4 |
Pagination | e312-7 |
Date Published | 2010 Oct |
ISSN | 1879-2472 |
Keywords | Adenosine Monophosphate, Animals, Apolipoproteins E, Blood Platelets, Chlorides, Female, Ferric Compounds, Fibrinogen, Gene Deletion, Mice, Mice, Inbred C57BL, Purinergic P2Y Receptor Antagonists, Receptors, Purinergic P2Y12, Thrombosis, Tobacco Smoke Pollution |
Abstract | INTRODUCTION: 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. |
DOI | 10.1016/j.thromres.2010.03.010 |
Alternate Journal | Thromb. Res. |
PubMed ID | 20451958 |
PubMed Central ID | PMC2921009 |
Grant List | R01 HL078663 / HL / NHLBI NIH HHS / United States HL078663 / HL / NHLBI NIH HHS / United States R01 HL074219 / HL / NHLBI NIH HHS / United States HL0870166 / HL / NHLBI NIH HHS / United States HL074219 / HL / NHLBI NIH HHS / United States P01 HL080166 / HL / NHLBI NIH HHS / United States |