Investigations of human platelet-type 12-lipoxygenase: role of lipoxygenase products in platelet activation

Ikei, Kenneth; Yeung, Jennifer; Apopa, Patrick L.; Ceja, Jesús; Vesci, Joanne; Holman, Theodore R.; Holinstat, Michael

doi:10.1194/jlr.m026385

Cited by 80 publications

(100 citation statements)

References 63 publications

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“…Qualitatively, these findings support the hypothesis that the CYP-mediated epoxygenation of ω-6 and ω-3 endocannabinoids alters cannabinoid receptor activation, generally producing CB2-preferring metabolites similar to AEA and 2-AG (22,26 (Fig. 5A) (46). These inhibitory effects were not observed in thrombin-, PAR4-AP-, collagen-, or U46619-induced platelet aggregation (SI Appendix, Fig.…”

Section: Resultssupporting

confidence: 71%

Anti-inflammatory ω-3 endocannabinoid epoxides

McDougle

Watson

Abdeen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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139

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Clinical studies suggest that diets rich in ω-3 polyunsaturated fatty acids (PUFAs) provide beneficial anti-inflammatory effects, in part through their conversion to bioactive metabolites. Here we report on the endogenous production of a previously unknown class of ω-3 PUFA–derived lipid metabolites that originate from the crosstalk between endocannabinoid and cytochrome P450 (CYP) epoxygenase metabolic pathways. The ω-3 endocannabinoid epoxides are derived from docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) to form epoxyeicosatetraenoic acid-ethanolamide (EEQ-EA) and epoxydocosapentaenoic acid-ethanolamide (EDP-EA), respectively. Both EEQ-EAs and EDP-EAs are endogenously present in rat brain and peripheral organs as determined via targeted lipidomics methods. These metabolites were directly produced by direct epoxygenation of the ω-3 endocannabinoids, docosahexanoyl ethanolamide (DHEA) and eicosapentaenoyl ethanolamide (EPEA) by activated BV-2 microglial cells, and by human CYP2J2. Neuroinflammation studies revealed that the terminal epoxides 17,18-EEQ-EA and 19,20-EDP-EA dose-dependently abated proinflammatory IL-6 cytokines while increasing anti-inflammatory IL-10 cytokines, in part through cannabinoid receptor-2 activation. Furthermore the ω-3 endocannabinoid epoxides 17,18-EEQ-EA and 19,20-EDP-EA exerted antiangiogenic effects in human microvascular endothelial cells (HMVEC) and vasodilatory actions on bovine coronary arteries and reciprocally regulated platelet aggregation in washed human platelets. Taken together, the ω-3 endocannabinoid epoxides’ physiological effects are mediated through both endocannabinoid and epoxyeicosanoid signaling pathways. In summary, the ω-3 endocannabinoid epoxides are found at concentrations comparable to those of other endocannabinoids and are expected to play critical roles during inflammation in vivo; thus their identification may aid in the development of therapeutics for neuroinflammatory and cerebrovascular diseases.

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Section: Resultssupporting

confidence: 71%

Anti-inflammatory ω-3 endocannabinoid epoxides

McDougle

Watson

Abdeen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

139

156

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“…The major enzymes for the biosynthesis of DHA-derived mediators in human MCs and PMN are 5-LO, h15-LO-1, and P450; while in mouse Mfs, they are 5-LO, L12-LO, and P450; in PLT, they are P12-LO and P450 (Ikei et al, 2012; Serhan et al, 2009). Our data suggest that the h15-LO-1 in human leukocytes, L12-LO in mouse Mfs, and P12-LO in PLT were responsible for DHA 14 S -hydroxylation for 14 S ,22-diHDHA biosynthesis.…”

Section: Discussionmentioning

confidence: 99%

Maresin-like Lipid Mediators Are Produced by Leukocytes and Platelets and Rescue Reparative Function of Diabetes-Impaired Macrophages

Hong

Lü

Tian

et al. 2014

Chemistry & Biology

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SUMMARY Non-healing diabetic wounds are associated with impaired macrophage (Mf) function. Leukocytes and platelets (PLT) play crucial roles in wound healing by poorly understood mechanisms. Here, we report identification and characterization of novel maresin-like(L) mediators 14,22-dihydroxy-docosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acids, 14S,22-diHDHA (maresin-L1) and 14R,22-diHDHA (maresin-L2) that are produced by leukocytes and PLT and involved in wound healing. We show that 12-lipoxygenase-initiated 14S-hydroxylation or cytochrome P450 catalyzed 14R-hydroxylation, and P450-initiated ω(22)-hydroxylation are required for maresin-Ls biosynthesis. Maresin-L treatment restores reparative functions to diabetic Mfs, suggesting that maresin-Ls act as autocrine/paracrine factors responsible for, at least in part, the reparative functions of leukocytes and PLT in wounds. Additionally, maresin-L ameliorates Mfs inflammatory activation and have the potential to suppress the chronic inflammation in diabetic wounds caused by activation of Mfs. These findings provide initial insights into maresin-L biosynthesis and mechanism of action, and potentially offer a therapeutic option for better treatment of diabetic wounds.

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“…3 Currently approved antiplatelet therapies inhibit platelet function by targeting platelet enzymes, receptors, and glycoproteins. 4 While these therapeutic approaches limit platelet function, they often result in a concomitant increased risk of bleeding. Therefore, a need exists for the identification of novel antiplatelet therapeutic targets that limit bleeding.…”

Section: Introductionmentioning

confidence: 99%

First Selective 12-LOX Inhibitor, ML355, Impairs Thrombus Formation and Vessel Occlusion In Vivo With Minimal Effects on Hemostasis

Adili

Tourdot

Mast

et al. 2017

ATVB

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Objective Adequate platelet reactivity is required for maintain hemostasis. However, excessive platelet reactivity can also lead to the formation of occlusive thrombi. 12-lipoxygenase (12-LOX), an oxygenase highly expressed in the platelet, has been demonstrated to regulate platelet function and thrombosis ex vivo, supporting a key role for 12-LOX in the regulation of in vivo thrombosis. However, the ability to pharmacologically target 12-LOX in vivo has not been established to date. Here, we studied the effect of the first highly selective 12-LOX inhibitor, ML355, on in vivo thrombosis and hemostasis. Approach and Results ML355 dose-dependently inhibited human platelet aggregation and 12-LOX oxylipin production, as confirmed by mass spectrometry. Interestingly, the antiplatelet effects of ML355 were reversed following exposure to high concentrations of thrombin in vitro. Ex vivo flow chamber assays confirmed that human platelet adhesion and thrombus formation at arterial shear over collagen were attenuated in whole blood treated with ML355 comparable to aspirin. Oral administration of ML355 in mice showed reasonable plasma drug levels by pharmacokinetic assessment. ML355 treatment impaired thrombus growth and vessel occlusion in FeCl3-induced mesenteric and laser-induced cremaster arteriole thrombosis models in mice. Importantly, hemostatic plug formation and bleeding following treatment with ML355 was minimal in mice in response to laser ablation on the saphenous vein or in a cremaster microvasculature laser-induced rupture model. Conclusions Our data strongly supports 12-LOX as a key determinant of platelet reactivity in vivo and inhibition of platelet 12-LOX with ML355 may represent a new class of antiplatelet therapy.

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Investigations of human platelet-type 12-lipoxygenase: role of lipoxygenase products in platelet activation

Cited by 80 publications

References 63 publications

Anti-inflammatory ω-3 endocannabinoid epoxides

Anti-inflammatory ω-3 endocannabinoid epoxides

Maresin-like Lipid Mediators Are Produced by Leukocytes and Platelets and Rescue Reparative Function of Diabetes-Impaired Macrophages

First Selective 12-LOX Inhibitor, ML355, Impairs Thrombus Formation and Vessel Occlusion In Vivo With Minimal Effects on Hemostasis

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