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Arterioscler Thromb Vasc Biol ; 36(10): 2068-77, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27470510

RESUMEN

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 Gαs-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.


Asunto(s)
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Ácido 8,11,14-Eicosatrienoico/farmacología , Araquidonato 12-Lipooxigenasa/sangre , Plaquetas/efectos de los fármacos , Cromograninas/sangre , Fibrinolíticos/farmacología , Subunidades alfa de la Proteína de Unión al GTP Gs/sangre , Activación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/farmacología , Trombosis/prevención & control , Ácido 8,11,14-Eicosatrienoico/metabolismo , Animales , Araquidonato 12-Lipooxigenasa/deficiencia , Araquidonato 12-Lipooxigenasa/genética , Plaquetas/metabolismo , Moléculas de Adhesión Celular/sangre , AMP Cíclico/sangre , Proteínas Quinasas Dependientes de AMP Cíclico/sangre , Modelos Animales de Enfermedad , Fibrinolíticos/metabolismo , Humanos , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Microfilamentos/sangre , Oxidación-Reducción , Fosfoproteínas/sangre , Fosforilación , Agregación Plaquetaria/efectos de los fármacos , Complejo Shelterina , Transducción de Señal/efectos de los fármacos , Proteínas de Unión a Telómeros/sangre , Trombosis/sangre , Trombosis/enzimología , Trombosis/genética , Factores de Tiempo
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