Preeclampsia activates 15-lipoxygenase and its metabolite 15-hydroxyeicosatetraenoic acid enhances constriction in umbilical arteries

Wang, Yuguang; Zhu, Daling; An, Yuan; Sun, Jin; Cai, Lu; Zheng, Jianhua

doi:10.1016/j.plefa.2011.10.006

Cited by 10 publications

(14 citation statements)

References 16 publications

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“…For example, angiotensin II, aldosterone, PDGF, TGF-β, IL-8, growth hormone-releasing peptide-2, peroxisome proliferator-activated receptor-γ agonist and high glucose increase 15-LO expression or rodent 12/15-LO expression in cultured smooth muscle cells or mesangial cells when compared with untreated cells 90–96 . 15-LO expression is also increased in human umbilical arteries from patients with pre-eclampsia compared to normal patients 97 .…”

Section: Conditions and Endogenous Chemicals Regulating 15-lo And Iedmentioning

confidence: 88%

Inducible Endothelium-derived Hyperpolarizing Factor

Campbell¹,

Gauthier²

2013

Journal of Cardiovascular Pharmacology

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Endothelium-derived hyperpolarizing factors (EDHFs) regulate vascular tone by contributing to the vasorelaxations to shear stress and endothelial agonists such as bradykinin and acetylcholine. 15(S)-Hydroxy-11,12-epoxyeicosatrienoic acid (15-H-11,12-EETA) and 11(R),12(S),15(S)-trihydroxyeicosatrienoic acid (11,12,15-THETA) are endothelial metabolites of the 15-lipoxygenase (15-LO) pathway of arachidonic acid metabolism and are EDHFs. 11,12,15-THETA activates small conductance, calcium-activated potassium channels on smooth muscle cells causing membrane hyperpolarization and relaxation. Expression levels of 15-LO in the endothelium regulate the activity of the 15-LO/15-H-11,12-EETA/11,12,15-THETA pathway and its contribution to vascular tone. Regulation of its expression is by transcriptional, translational and epigenetic mechanisms. Hypoxia, hypercholesterolemia, atherosclerosis, anemia, estrogen, interleukins and possibly other hormones increase 15-LO expression. An increase in 15-LO results in increased synthesis of 15-H-11,12-EETA and 11,12,15-THETA, increased membrane hyperpolarization and enhanced contribution to relaxation by endothelial agonists. Thus, the 15-LO pathway represents the first example of an inducible EDHF. In addition to 15-LO metabolites, a number of chemicals have been identified as EDHFs and their contributions to vascular tone vary with species and vascular bed. The reason for multiple EDHFs has evaded explanation. However, EDHFs functioning as constitutive EDHFs or inducible EDHFs may explain the need for chemically and biochemically distinct pathways for EDHF activity and the variation in EDHFs between species and vascular beds. This new EDHF classification provides a framework for understanding EDHF activity in physiological and pathological conditions.

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Section: Conditions and Endogenous Chemicals Regulating 15-lo And Iedmentioning

confidence: 88%

Inducible Endothelium-derived Hyperpolarizing Factor

Campbell¹,

Gauthier²

2013

Journal of Cardiovascular Pharmacology

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“…The initial steps in the SPM biosynthetic pathway are mediated by 5-lipoxygenase (5-LOX) or CYP450 which generate 18-HEPE from EPA, and 15-LOX or aspirin-acetylated prostaglandin G/Hsynthase 2 (PTGS2/COX2) which generates 17-HDHA from DHA (Bannenberg & Serhan 2010). The placenta has significant amounts of both 5-and 15-LOX activity (Mitchell & Grzyboski 1987, Datta & Kulkarni 1994, Wang et al 2012. Our findings expand the range of LOXderived metabolites identified in the placenta to include the n-3 PUFA-derived SPMs.…”

Section: Discussionmentioning

confidence: 99%

“…Our findings expand the range of LOXderived metabolites identified in the placenta to include the n-3 PUFA-derived SPMs. Interestingly, 15-LOX levels are increased in preeclamptic placentas (Johnson et al 1998, Wang et al 2012, raising the possibility that SPM production in the placentas of women with preeclampsia might be particularly enhanced with maternal DHA supplementation. Studies on circulating and placental SPM levels in preeclampsia might provide some interesting insights into its pathophysiology.…”

Section: Discussionmentioning

confidence: 99%

Effects of maternal n-3 fatty acid supplementation on placental cytokines, pro-resolving lipid mediators and their precursors

Keelan¹,

Mas²,

D’Vaz³

et al. 2015

Reproduction

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The aim of this study was to determine whether supplementation with fish oil-derived n-3 polyunsaturated fatty acids (n-3 PUFA) during pregnancy modifies placental PUFA composition, the accumulation of specialised pro-resolving lipid mediators (SPMs, specifically resolvins (Rv), protectins (PD) and upstream precursors) and inflammatory gene expression. Placentas were collected from women (nZ51) enrolled in a randomised, placebo controlled trial of n-3 PUFA supplementation from 20-week gestation. Lipids were extracted for fatty acid analysis and SPMs were quantitated by mass spectrometry. Gene expression was determined by qRT-PCR. Using multiple regression analysis, data were correlated for placental n-3 PUFA and SPM levels with PUFA levels in maternal and cord blood erythrocytes. Supplementation with n-3 PUFAs increased placental docosahexaenoic acid (DHA) levels, but not eicosapentaenoic acid (EPA) levels (P!0.05), and increased the levels of the SPM precursors 18-hydroxyeicosapentaenoic acid and 17-hydroxydocosahexaenoic acid (17-HDHA) by two-to threefold (P!0.0005). RvD1, 17R-RvD1, RvD2 and PD1 were detectable in all placentas, but concentrations were not significantly increased by n-3 PUFA supplementation. Placental DHA levels were positively associated with maternal and cord DHA levels (P!0.005), and with placental 17-HDHA concentrations (P!0.0001). Placental mRNA expression of PTGS2, IL1b, IL6 and IL10 was unaffected by n-3 PUFA supplementation, but TNFa expression was increased by 14-fold (P!0.05). We conclude that n-3 PUFA supplementation in pregnancy i) enhances placental accumulation of DHA and SPM precursors, ii) does not alter placental EPA levels, and iii) has no stimulatory effects on inflammatory gene expression. Further studies are required to ascertain the biological significance of SPMs in the placenta and the potential immunomodulatory effects of elevating placental SPM levels.

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“…The HETEs and LTB4 are mainly involved in the regulation of inflammation, vasoconstriction, and platelet aggregation. 15-HETE can increase the contraction of smooth muscle cells in human umbilical artery rings [12]. Additionally, the inflammatory state of the placenta during pregnancy could promote the synthesis of 5-HETE inside the placenta [11].…”

Section: Discussionmentioning

confidence: 99%