12(S)-HETrE, a 12-Lipoxygenase Oxylipin of Dihomo-γ-Linolenic Acid, Inhibits Thrombosis via Gα s Signaling in Platelets
| Autor: | Reheman Adili, Theodore R. Holman, Pilar Fernandez-Perez, Johnny Yu, Michael Holinstat, Benjamin E. Tourdot, Cody J. Freedman, Abigail R. Green, Jennifer Yeung |
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| Rok vydání: | 2016 |
| Předmět: |
Blood Platelets
0301 basic medicine Time Factors Platelet Aggregation Telomere-Binding Proteins 030204 cardiovascular system & hematology Pharmacology Arachidonate 12-Lipoxygenase Shelterin Complex 03 medical and health sciences chemistry.chemical_compound Lipoxygenase 8 11 14-Eicosatrienoic Acid 0302 clinical medicine Fibrinolytic Agents Chromogranins Cyclic AMP GTP-Binding Protein alpha Subunits Gs Animals Humans Platelet Platelet activation Phosphorylation Mice Knockout chemistry.chemical_classification Dihomo-γ-linolenic acid biology Microfilament Proteins Thrombosis Oxylipin Phosphoproteins Platelet Activation Cyclic AMP-Dependent Protein Kinases Mice Inbred C57BL Disease Models Animal 030104 developmental biology Biochemistry chemistry biology.protein Platelet aggregation inhibitor Cardiology and Cardiovascular Medicine Cell Adhesion Molecules Oxidation-Reduction Platelet Aggregation Inhibitors Fibrinolytic agent Signal Transduction Polyunsaturated fatty acid |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology. 36:2068-2077 |
| ISSN: | 1524-4636 1079-5642 |
| Popis: | Objective— Dietary supplementation with polyunsaturated fatty acids has been widely used for primary and secondary prevention of cardiovascular disease in individuals at risk; however, the cardioprotective benefits of polyunsaturated fatty acids remain controversial because of lack of mechanistic and in vivo evidence. We present direct evidence that an omega-6 polyunsaturated fatty acid, dihomo-γ-linolenic acid (DGLA), exhibits in vivo cardioprotection through 12-lipoxygenase (12-LOX) oxidation of DGLA to its reduced oxidized lipid form, 12(S)-hydroxy-8Z,10E,14Z-eicosatrienoic acid (12(S)-HETrE), inhibiting platelet activation and thrombosis. Approach and Results— DGLA inhibited ex vivo platelet aggregation and Rap1 activation in wild-type mice, but not in mice lacking 12-LOX expression (12-LOX −/− ). Similarly, wild-type mice treated with DGLA were able to reduce thrombus growth (platelet and fibrin accumulation) after laser-induced injury of the arteriole of the cremaster muscle, but not 12-LOX −/− mice, supporting a 12-LOX requirement for mediating the inhibitory effects of DGLA on platelet-mediated thrombus formation. Platelet activation and thrombus formation were also suppressed when directly treated with 12(S)-HETrE. Importantly, 2 hemostatic models, tail bleeding and arteriole rupture of the cremaster muscle, showed no alteration in hemostasis after 12(S)-HETrE treatment. Finally, the mechanism for 12(S)-HETrE protection was shown to be mediated via a Gα s -linked G-protein–coupled receptor pathway in human platelets. Conclusions— This study provides the direct evidence that an omega-6 polyunsaturated fatty acid, DGLA, inhibits injury-induced thrombosis through its 12-LOX oxylipin, 12(S)-HETrE, which strongly supports the potential cardioprotective benefits of DGLA supplementation through its regulation of platelet function. Furthermore, this is the first evidence of a 12-LOX oxylipin regulating platelet function in a Gs α subunit–linked G-protein–coupled receptor–dependent manner. |
| Databáze: | OpenAIRE |
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