8-11-14-eicosatrienoic-acid and Thrombosis

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Blood Vessels; Eicosanoic Acids; Eicosapentaenoic Acid; Endothelium; Fatty Acids, Unsaturated; Fibrinolytic Agents; Hemostasis; Humans; Phospholipids; Prostaglandins; Rabbits; Thrombosis

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Arachidonic Acid; Arachidonic Acids; Arteriosclerosis; Blood Platelets; Dietary Fats; Eicosanoic Acids; Eicosapentaenoic Acid; Fatty Acids; Fatty Acids, Unsaturated; Humans; Linoleic Acid; Linoleic Acids; Linolenic Acids; Platelet Aggregation; Prostaglandins; Thrombin; Thrombosis

Epoxyeicosatrienoic acids (EETs), which are synthesized from arachidonic acid by cytochrome P450 epoxygenases, function primarily as autocrine and paracrine effectors in the cardiovascular system. So far, most research has focused on the vasodilatory, anti-inflammatory, anti-apoptotic and mitogenic properties of EETs in the systemic circulation. However, whether EETs could suppress tissue factor (TF) expression and prevent thrombus formation remains unknown. Here we utilized in vivo and in vitro models to investigate the effects and underlying mechanisms of exogenously EETs on LPS induced TF expression and inferior vein cava ligation induced thrombosis. We observed that the thrombus formation rate and the size of the thrombus were greatly reduced in 11,12-EET treated mice，accompanied by decreased TF and inflammatory cytokines expression. Further in vitro studies showed that by enhancing p38 MAPK activation and subsequent tristetraprolin (TTP) phosphorylation, LPS strengthened the stability of TF mRNA and induced increased TF expression. However, by strengthening PI3K-dependent Akt phosphorylation, which acted as a negative regulator of p38-TTP signaling pathway，11,12-EET reduced LPS-induced TF expression in monocytes. In addition, 11,12-EET inhibited LPS-induced NF-κB nuclear translocation by activating the PI3K/Akt pathway. Further study indicated that the inhibitory effect of 11,12-EET on TF expression was mediated by antagonizing LPS-induced activation of thromboxane prostanoid receptor. In conclusion, our study demonstrated that 11,12-EET prevented thrombosis by reducing TF expression and targeting the CYP2J2 epoxygenase pathway may represent a novel approach to mitigate thrombosis related diseases.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; Lipopolysaccharides; Mice; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; RNA Stability; Signal Transduction; Thromboplastin; Thrombosis

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.. 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.. 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.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Arachidonate 12-Lipoxygenase; Blood Platelets; Cell Adhesion Molecules; Chromogranins; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Disease Models, Animal; Fibrinolytic Agents; GTP-Binding Protein alpha Subunits, Gs; Humans; Mice, Inbred C57BL; Mice, Knockout; Microfilament Proteins; Oxidation-Reduction; Phosphoproteins; Phosphorylation; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Shelterin Complex; Signal Transduction; Telomere-Binding Proteins; Thrombosis; Time Factors

Topics: 8,11,14-Eicosatrienoic Acid; Adenosine Diphosphate; Animals; Arachidonic Acids; Blood Platelets; Collagen; Epinephrine; Fatty Acids, Unsaturated; Humans; Linolenic Acids; Peroxides; Platelet Adhesiveness; Platelet Aggregation; Prostaglandins; Prostaglandins E; Rats; Thrombosis