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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Johnson, E. N. Funk, C. D. Brass, L. F. |
| Description | Author Affiliation: Johnson EN ( Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.); |
| Abstract | Arachidonic acid metabolism is one of several mechanisms culminating in the production of an agonist for platelet activation and recruitment. Although the proaggregatory role of thromboxane A2, a product of the aspirin-inhibitable cyclooxygenase, is well established, relatively little is known regarding the biological importance of arachidonic acid metabolism via the 12-lipoxygenase (P-12LO) pathway to 12-hydro(pero)xyeicosatetraenoic acid. We observed that platelets obtained from mice in which the P-12LO gene has been disrupted by gene targeting (P-12LO-/-) exhibit a selective hypersensitivity to ADP, manifested as a marked increase in slope and percent aggregation in ex vivo assays and increased mortality in an ADP-induced mouse model of thromboembolism. The hyperresponsiveness to ADP is independent of dense granule release, cyclooxygenase-derived eicosanoid synthesis, and protein kinase C activity. The addition of 12-hydroxyeicosatetraenoic acid to P-12LO-/- platelet-rich plasma rescues the hyperresponsive phenotype resulting in a diminished ADP-induced aggregation profile. The enhanced ADP sensitivity of P-12LO-/- mice appears to reveal a mechanism by which a product of the P-12LO pathway suppresses platelet activation by ADP. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 6 |
| Volume Number | 95 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 1998-04-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Adenosine Diphosphate Pharmacology Arachidonate 12-Lipoxygenase Deficiency Blood Platelets Drug Effects Platelet Aggregation Genetics Thromboembolism Etiology 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid Biosynthesis Animals Arachidonic Acid Metabolism Disease Models, Animal Dose-Response Relationship, Drug Gene Targeting Mice Mice, Mutant Strains Second Messenger Systems Mortality Research Support, U.S. Gov't, P.H.S. Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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