Enrichment of platelet phospholipids with eicosapentaenoic acid and docosahexaenoic acid inhibits thromboxane A2/prostaglandin H2 receptor binding and function.
Human platelet lipids were enriched in vitro with different amounts of either docosahexaenoic acid (22:6n-3), eicosapentaenoic acid (20:5n-3) or linoleic acid (18:2n-6). Of the total fatty acid incorporated, between 82 and 95% was associated with the phospholipid (PL) fraction, with the remainder as either neutral lipid or hydroxy fatty acid. Within the PL fraction, the majority (64% of total) of each fatty acid was incorporated into phosphatidylcholine. It was found that platelet aggregation induced by the thromboxane A2/prostaglandin H2 mimetic (15S)-hydroxy-11,9-(epoxymethano)prosta-5Z,13E-dienoic acid (U46619) was inhibited after PL enrichment with 22:6n-3 or 20:5n-3, but not after 18:2n-6 enrichment. The specificity of 22:6n-3 and 20:5n-3 for U46619 activation was demonstrated by the finding that neither fatty acid significantly inhibited thromboxane A2/prostaglandin H2-independent aggregation induced by A23187 or thrombin. Furthermore, enrichment with 22:6n-3 or 20:5n-3 resulted in inhibition of [3H]U46619 specific binding, while enrichment with 18:2n-6 did not affect binding. Scatchard analysis revealed that thromboxane A2/prostaglandin H2 receptor affinity for [3H]U46619 decreased 4.8-fold following 22:6n-3 incorporation. These results demonstrate that platelet phospholipid enrichment with 22:6n-3 or 20:5n-3 results in a selective inhibition of thromboxane A2/prostaglandin H2 receptor function.
Swann
P G
PG
Department of Pharmacology, University of Illinois, Chicago 60612.
Parent
C A
CA
Croset
M
M
Fonlupt
P
P
Lagarde
M
M
Venton
D L
DL
Le Breton
G C
GC
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D001792:Blood Platelets / Q000502:physiology*; D000001:Calcimycin / Q000494:pharmacology; D004281:Docosahexaenoic Acids / Q000097:blood*; D015118:Eicosapentaenoic Acid / Q000097:blood*; D006801:Humans; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008563:Membrane Lipids / Q000097:blood; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic / Q000378:metabolism / Q000494:pharmacology; D011982:Receptors, Prostaglandin / Q000097:blood* / Q000378:metabolism; D017482:Receptors, Thromboxane; D013917:Thrombin / Q000494:pharmacology
D008563:Membrane Lipids; D010975:Platelet Aggregation Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D004281:Docosahexaenoic Acids; D000001:Calcimycin; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D015118:Eicosapentaenoic Acid; D013917:Thrombin; D007213:Indomethacin