title: Aspirin inhibits the production of proangiogenic 15(S)-HETE by platelet cyclooxygenase-1.
abstract: Regular consumption of low-dose aspirin reduces the occurrence of colorectal, esophageal, stomach, and gastrointestinal cancers. The underlying mechanism is unknown but may be linked to inhibition of angiogenesis. Because the effective doses of aspirin are consistent with the inhibition of cyclooxygenase-1 in platelets, we used liquid chromatography with tandem mass spectrometry analyses and immunoassays of human platelet releasates coupled with angiogenesis assays to search for the mediators of these effects. Blood or platelet-rich plasma from healthy volunteers stimulated with platelet activators produced a broad range of eicosanoids. Notably, preincubation of platelets with aspirin, but not with a P2Y12receptor antagonist, caused a marked reduction in the production of 11-hydroxyeicosatetraenoic acid (HETE) and 15(S)-HETE, in addition to prostanoids such as thromboxane A2Releasates from activated platelets caused cell migration and tube formation in cultured human endothelial cells and stimulated the sprouting of rat aortic rings in culture. These proangiogenic effects were absent when platelets were treated with aspirin but returned by coincubation with exogenous 15(S)-HETE. These results reveal 15(S)-HETE as a major platelet cyclooxygenase-1 product with strong proangiogenic effects. Thus, 15(S)-HETE represents a potential target for the development of novel antiangiogenic therapeutics, and blockade of its production may provide a mechanism for the anticancer effects of aspirin.-Rauzi, F., Kirkby, N. S., Edin, M. L., Whiteford, J. Zeldin, D. C., Mitchell, J. A., Warner, T. D. Aspirin inhibits the production of proangiogenic 15(S)-HETE by platelet cyclooxygenase-1.
authors.affiliation: The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Francesca
authors.initials: F
authors.lastname: Rauzi
authors.affiliation: The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.|National Heart and Lung Institute, Imperial College London, London, United Kingdom; and.
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Kirkby
authors.affiliation: National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Edin
authors.affiliation: The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Whiteford
authors.affiliation: National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
authors.forename: Darryl C
authors.initials: DC
authors.lastname: Zeldin
authors.affiliation: National Heart and Lung Institute, Imperial College London, London, United Kingdom; and.
authors.forename: Jane A
authors.initials: JA
authors.lastname: Mitchell
authors.affiliation: The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom; t.d.warner@qmul.ac.uk.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Warner
mesh_terms: D001241:Aspirin / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects*; D002478:Cells, Cultured; D051545:Cyclooxygenase 1 / Q000187:drug effects / Q000378:metabolism*; D015777:Eicosanoids / Q000378:metabolism; D004727:Endothelium / Q000187:drug effects*; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects*
chemical_list: D015777:Eicosanoids; D006893:Hydroxyeicosatetraenoic Acids; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D051545:Cyclooxygenase 1; D001241:Aspirin
keywords: angiogenesis; eicosanoids; endothelium; prostaglandins