Oxidized Low-Density Lipoprotein and Cell Adhesion Molecules Following Exercise Training.

Elevated oxidized low-density lipoprotein (ox-LDL) and cell adhesion molecules are associated with inflammation and atherosclerosis. The role of exercise in circulating ox-LDL, enzyme mediators, and cell adhesion molecules are not clearly understood in obesity. As a randomized controlled design, 27 obese (BMI>30 kg/m2) sedentary men (N=13) and women (N=14) were randomly assigned to either an exercise (N=15) or a control (N=12) group. The exercise group performed a 60-min supervised treadmill exercise at moderate intensity (70% of HRmax) for 3 days per week for 4 weeks, while the control group did not exercise. Overnight fasting blood samples were collected before and after the study period to analyze serum lipids, lipoprotein-cholesterol, ox-LDL, 12- and 15-lipoxygenases, myeloperoxidase (MPO), and soluble vascular cell adhesion molecules-1 and intercellular adhesion molecule-1. Moderate-intensity exercise training lowered both ox-LDL (from 44.76±1.99 to 38.51±1.99 U/L, p=0.032) and MPO (from 31.48±2.20 to 23.09±2.20 ng/mL, p=0.010), without significantly altering body weight, other parameters of serum lipids and lipoproteins, or soluble cell adhesion molecules. Moderate intensity exercise training reduced the levels of ox-LDL and MPO, indicating a reduced risk for developing CVD and additional protection to the possible metabolic complications associated with obesity.

[Reversed changes of the 15-lipoxygenase product lipoxin A4 and the 5-lipoxygenase product leukotriene C4 in children with asthma].

OBJECTIVE: To investigate the expressions of 15- and 5-lipoxygenases in leukocytes and the changes of the levels of blood lipoxin A4 (LXA4) and leukotriene C4 (LTC4) in children with asthma. METHODS: The mRNA levels of 15- and 5-lipoxygenases in leukocytes were assessed by RT-PCR, and the levels of blood LXA4 and LTC4 were determined by ELISA, in 106 children with mild, moderate and severe asthma. Forty healthy children served as the controls. RESULTS: In children with mild, moderate and severe asthma, the relative mRNA levels of 15-lipoxygenase in leukocytes were 1.78 ± 0.56, 1.28 ± 0.45 and 0.58 ± 0.22 (F = 16.72, P < 0.01), respectively, and all were higher than that of the controls (0.26 ± 0.12, P < 0.05). The levels of blood LXA4 were (5.52 ± 1.97), (1.86 ± 0.72) and (0.81 ± 0.36) µg/L (F = 22.59, P < 0.01), respectively, decreasing with the severity of asthma, and all were higher than that of the controls [(0.04 ± 0.01) µg/L, P < 0.05]. There was a positive correlation between PEF, FEV(1) and blood LXA4. The relative levels of 5-lipoxygenase mRNA in leukocytes were 0.26 ± 0.12, 0.79 ± 0.34 and 1.21 ± 0.52, respectively in children with asthma of mild, moderate and severe degree (F = 18.64, P < 0.01), which showed an increase with the severity of the disease, and all of which were higher than that of the controls (0.12 ± 0.05, P < 0.05). The levels of blood LTC4 were (22.4 ± 8.2), (54.6 ± 28.4) and (118.7 ± 41.1) ng/L (F = 25.91, P < 0.01), respectively, also showing an increase with the severity of asthma, and were higher than that of the controls [(6.8 ± 2.5) ng/L, P < 0.05]. There was a negative correlation between PEF, FEV1 and blood LTC4. CONCLUSION: The reversed changes of 15-lipoxygenase product LXA4 and 5-lipoxygenase product LTC4 in children with asthma of mild, moderate and severe degree suggests that insufficiency of LXA4, an physiological antagonist to leukotrienes, and an overproduction of LTC4, may be involved in the pathogenesis of worsening of asthma in children.

15-lipoxygenase-1 in colorectal cancer: a review.

OBJECTIVE: Enzymes involved in the oxidative metabolism of n-6 polyunsaturated fatty acids, like lipoxygenase (LOX) and cyclooxygenase (COX), are significant in the pathogenesis of colorectal cancer. Of these enzymes, 15-LOX-1 is expressed in colon. Aim of this article is to describe the role and regulation of 15-LOX-1 in colorectal cancer and highlight its importance in cancer therapeutics. METHODS: For our electronic literature research in PubMed and MEDLINE, key words related to 15-LOX-1 and colorectal cancer were used to find articles for this review. RESULTS: From the evidences, we believe that 15-LOX-1 has anti-carcinogenic effects in colorectal cancer, dependent or independent of its metabolites, and is manifested through downstream pathways involving cGMP, PPAR, p53, p21 and NAG-1, increasing apoptosis and decreasing proliferation in cancer cells. Regulation of 15-LOX-1 expression is achieved at transcription level by global histone acetylation and may also be dependent on GATA-6, IL-4 and IL-13. Positive relationship exists between 15-LOX-1 and survival in colorectal cancer. CONCLUSION: Evidences strongly support that therapeutic modulation of 15-LOX-1 may be a key to the treatment of colorectal cancer. However, it is still undecided whether the up-regulation of 15-LOX-1 alone can be sufficient to treat colorectal cancer and further studies are awaited.

Elevated levels of 15-lipoxygenase-1 contribute to the abnormal phenotypes of osteoblasts in human osteoarthritis.

AIMS: 15-lipoxygenase-1 (15-LOX-1) plays a vital role in aggravating the inflammatory response in various pathological processes, including osteoarthritis (OA). Abnormal osteoblast phenotypes including elevated runt-related transcription factor 2 (RUNX2), collagen type 1 alpha 1 (COL1), and osteocalcin (OCN) lead to osteosclerosis of the subchondral bone, which eventually causes OA. However, the pathogenesis of OA is poorly defined, and it is unclear if 15-LOX-1 induces osteoblast abnormal phenotypes in OA. Therefore, this study aimed to determine the roles of 15-LOX-1 on the abnormal phenotypes present in osteoblasts of the subchondral bone in OA. MAIN METHODS: The expression levels of 15-LOX-1 were measured by Immunohistochemistry, qRT-PCR and western blotting from the OA subchondral bone osteoblasts. To further investigate the roles of 15-LOX-1 in abnormal phenotypes of osteoblasts and its mechanisms in OA, 15-LOX-1 siRNA or overexpressing lv-15-lox-1 were transfected into osteoblasts, respectively. The effects of 15-LOX-1 on abnormal phenotypes of osteoblasts in OA were assessed by qRT-PCR, and western blotting. We also examined the role of 15-LOX-1-inhibited autophagy in OA osteoblasts by qRT-PCR, and western blotting, transmission electron microscopy. KEY FINDINGS: The expression levels of 15-LOX-1 along with osteoblast phenotype markers such as RUNX2, COL1, and OCN were significantly increased in OA subchondral bone. Furthermore, 15-LOX-1 inhibited autophagy significantly upregulated the expression levels of RUNX2, COL1 and OCN through activated mTORC1. Similarly, treatment with autophagy inhibitors alleviated osteoblast abnormal phenotypes of osteoblasts in OA. SIGNIFICANCE: In conclusion, our results suggested that the expression of 15-LOX-1 on osteoblasts from the subchondral bone increased in OA. 15-LOX-1 inhibited autophagy by activated mTORC1, which in turn upregulated the markers of abnormal osteoblast phenotypes RUNX2, COL1, and OCN.

Substrate specificity changes for human reticulocyte and epithelial 15-lipoxygenases reveal allosteric product regulation.

Human reticulocyte 15-lipoxygenase (15-hLO-1) and epithelial 15-lipoxygenase (15-hLO-2) have been implicated in a number of human diseases, with differences in their substrate specificity potentially playing a central role. In this paper, we present a novel method for accurately measuring the substrate specificity of the two 15-hLO isozymes and demonstrate that both cholate and specific LO products affect substrate specificity. The linoleic acid (LA) product, 13-hydroperoxyoctadienoic acid (13-HPODE), changes the ( k cat/ K m) (AA)/( k cat/ K m) (LA) ratio more than 5-fold for 15-hLO-1 and 3-fold for 15-hLO-2, while the arachidonic acid (AA) product, 12-( S)-hydroperoxyeicosatetraenoic acid (12-HPETE), affects only the ratio of 15-hLO-1 (more than 5-fold). In addition, the reduced products, 13-( S)-hydroxyoctadecadienoic acid (13-HODE) and 12-( S)-hydroxyeicosatetraenoic acid (12-HETE), also affect substrate specificity, indicating that iron oxidation is not responsible for the change in the ( k cat/ K m) (AA)/( k cat/ K m) (LA) ratio. These results, coupled with the dependence of the 15-hLO-1 k cat/ K m kinetic isotope effect ( (D) k cat/ K m) on the presence of 12-HPETE and 12-HETE, indicate that the allosteric site, previously identified in 15-hLO-1 [Mogul, R., Johansen, E., and Holman, T. R. (1999) Biochemistry 39, 4801-4807], is responsible for the change in substrate specificity. The ability of LO products to regulate substrate specificity may be relevant with respect to cancer progression and warrants further investigation into the role of this product-feedback loop in the cell.

The role of expression and activity of 15-Lipoxygenase isoforms and related cytokines in patients with Multiple Sclerosis and healthy controls.

BACKGROUND: Multiple Sclerosis (MS) as an inflammatory multifactorial auto immune nervous system disease imposes devastating burden of morbidity worldwide. Among environmental and genetic factors, the relevance of inflammatory mediators in MS pathogenesis is well documented. 15-Lipoxygense enzyme and its derived products have received attention as possible mediators of inflammatory responses. The involvement of 15-Lipoxygense pathway in the pathogenesis of inflammatory diseases such as MS has yet to be illustrated which is perused in the current study. METHODS: The expression level of 15-Lipoxygense isoforms was assessed via Real-Time PCR in the peripheral blood mononuclear cells separated from patients with MS and healthy subjects. The level of 15-Lipoxygense products (15(S) HETE, 13(S) HODE) and related cytokines (IL4 and IL13) were evaluated using enzyme immunoassay kits in serum samples. RESULTS: Our results demonstrated that 15-Lipoxygense-1 and 15-Lipoxygense-2 expression levels were increased in patients suffering from MS comparing to healthy subjects which were more obvious in Relapsing-Remitting MS. The elevated levels of 15-Lipoxygense isoforms were accompanied with 15(S) HETE and 13(S) HODE enhancement in serum of patients and the IL 13 elevation but not IL4 was consistent with higher expression of 15-Lipoxygense. The diagnostic value of 15-Lipoxygense isoforms and products were considerable between patients and healthy groups. CONCLUSION: The possible effect of 15-Lipoxygense pathway in the regulation of inflammatory events may light up new therapeutic possibilities regarding MS pathogenesis.

CTRP5 promotes transcytosis and oxidative modification of low-density lipoprotein and the development of atherosclerosis.

BACKGROUND AND AIMS: Increased transcytosis of low-density lipoprotein (LDL) across the endothelium and oxidation of LDL deposited within the subendothelial space are crucial early events in atherogenesis. C1q/TNF-related protein (CTRP) 5 is a novel secreted glycoprotein and its biological functions are largely undefined. METHODS: Expression of CTRP5 was analyzed in sera and atherosclerotic plaques of patients with coronary artery disease (CAD). The role of CTRP5 in atherogenesis was investigated in vitro and in vivo. RESULTS: We found CTRP5 serum levels were higher in patients with than without CAD (247.26 ±â€¯61.71 vs. 167.81 ±â€¯68.08 ng/mL, p < 0.001), and were positively correlated with the number of diseased vessels (Spearman's r = 0.611, p < 0.001). Increased expression of CTRP5 was detected in human coronary endarterectomy specimens as compared to non-atherosclerotic arteries. Immunofluorescence further showed that CTRP5 was predominantly localized in the endothelium, infiltrated macrophages and smooth muscle cells in the neointima. In vivo and in vitro experiments demonstrated that CTRP5 promoted transcytosis of LDL across endothelial monolayers, as well as the oxidative modification of LDL in endothelial cells. Mechanistically, we found that CTRP5 up-regulated 12/15-lipoxygenase (LOX), a key enzyme in mediating LDL trafficking and oxidation, through STAT6 signaling. Genetic or pharmacological inhibition of 12/15-LOX dramatically attenuated the deposition of oxidized LDL in the subendothelial space and the development of atherosclerosis. CONCLUSIONS: These data indicate that CTRP5 is a novel pro-atherogenic cytokine and promotes transcytosis and oxidation of LDL in endothelial cells via up-regulation of 12/15-LOX.

Effect of palonosetron (5HT-3 antagonist) and pantoprazole (proton pump inhibitor) against surgical esophagitis induced by forestomach and pylorus ligation in albino rats.

This study was embarked upon to evaluate the effects of pantoprazole and palonosetron on experimental esophagitis in albino wistar rats. Groups of rats, fasted for 36 h, were subjected to pylorus and forestomach ligation, supervened by treatment with normal saline (3 ml/kg, po, sham control), esophagitis control (3 ml/kg, po), pantoprazole (30 mg/kg, po), palonosetron (0.5 mg/kg, po), and their combination. Animals were sacrificed after 12 h and appraised for the volume of gastric juices, total acidity, free acidity, and esophagitis index. Esophageal tissues were further figured out biochemically for markers of oxidative stress and inflammatory mediators. The combination therapy comparably inhibited the esophagitis index (52.86%), gastric volume (66.04%), free acidity (43.76%), and total acidity (42.60%) in comparison with toxic control. The combination therapy also subsidized the biochemical and inflammatory markers to the purview less than toxic control. The morphological changes were scrutinized by scanning electron microscopy and were observed to demonstrate momentous protection by the amalgamation therapy. Combination therapy with pantoprazole and palonosetron flaunted sententious protection against experimental esophagitis.

Conformational analysis of lipoxin A, lipoxin B and their trans-isomers.

Lipoxin A and lipoxin B (LXA and LXB) are formed from the oxygenation of arachidonic acid by interactions between the 5- and 15-lipoxygenases of human leukocytes. Each compound displays highly stereospecific biological actions. Here, we present a computational description of the following compounds: lipoxin A, (5S,6R,15S)-trihydroxy-7,9,13-trans-11-cis-eicosatetraenoic acid; 11-trans-lipoxin A, (5S,6R,15S)-trihydroxy-7,9,11,13-trans-eicosatetraenoic acid; lipoxin B, (5S,14R,15S)-trihydroxy-6,10,12-trans-8-cis-eicosatetraenoic acid; and 8-trans-lipoxin B, (5S,14R,15S)-trihydroxy-6,8,10,12-trans-eicosatetraenoic acid. The analyses considered van der Waals energy, electrostatic interactions, torsional potential, and alterations in electrostatic forces. Additional analyses were carried out with each of the four compounds forming complexes with one calcium ion. Each compound gave very different conformers. Both lipoxin A and lipoxin B can form globular conformations, while their all-trans isomers form rigid extended structures. When complexes with each of these compounds and one calcium ion were examined (i.e., (LXA)2Ca: (11-trans-LXA)2Ca), both LXA and LXB formed several flexible conformations including crumpled, wrapped or extended conformations. In this situation, LXA showed a higher probability than LXB to wrap around one Ca2+. In contrast, the two all-trans isomers always lead to extended conformations. Results from the present study illustrate that changes in the stereochemistry of LXA and LXB lead to unique conformations which may underlie the different biological actions of these compounds. Moreover, they indicate that the conformations of eicosanoids can change while in aqueous or hydrophobic environments (i.e., biomembranes).

Pathways for eosinophil lipid body induction: differing signal transduction in cells from normal and hypereosinophilic subjects.

Although lipid bodies, inducible cytoplasmic inclusions active in arachidonic acid metabolism, are abundant in activated leukocytes, including eosinophils, mechanisms for eosinophil lipid body formation are not certain. Eosinophils from hypereosinophilic syndrome (HES) donors contained about twice (approximately 18/cell) as many lipid bodies as eosinophils froin normal donors (approximately 10/cell). By immunocytochemistry both 5- and 15-lipoxygenases were localized at lipid bodies in HES eosinophils. Platelet-activating factor (PAF) induced rapid, receptor-mediated increases in lipid bodies in normal and HES eosinophils. Protein kinase C (PKC) inhibitors, chelerythrine and calphostin C, inhibited PAF-induced lipid body formation partially in normal and HES eosinophils. In HES, but not normal, eosinophils, PAF-induced lipid body formation was completely blocked by two tyrosine kinase inhibitors, herbimycin A and genistein, which were not acting on 5-lipoxygenase because they also blocked 5-HETE-induced lipid body formation in HES, and not normal, eosinophils. After 24 h culture with eosinophil growth factor cytokines [interleukin (IL)-3, IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF) or GM-CSF alone but not IL-5 or IL-3 alone], normal eosinophils were induced to exhibit an HES-like phenotype, including increased lipid body numbers and tyrosine kinase-dependent signaling for PAF-induced lipid body formation. Thus, signal transduction mechanisms involved in PAF-induced lipid body formation in eosinophils can be differentially recruited. Tyrosine kinase-dependent signaling is not involved in normal eosinophils, but is active in HES eosinophils and in normal eosinophils cultured with GM-CSF. PKC- and tyrosine kinase-dependent pathways are involved in the formation of eosinophil lipid bodies, which may facilitate enhanced synthesis of lipoxygenase-derived eicosanoids.

Evidence for the appearance of a reticulocyte population low in lipoxygenase mRNA during the recovery from a phenylhydrazine-induced anemia in rabbits.

It is shown that during recovery from a phenylhydrazine-induced anemia in rabbits a selective decrease in lipoxygenase mRNA takes place with a corresponding shut-off of the synthesis of the enzyme. It is suggested that a new population, 'recovery'-reticulocytes, makes its appearance in the peripheral blood. Their cells are more mature than the stress macroreticulocytes. A cell-free system prepared from the recovery-reticulocytes exhibits low endogenous synthesis of non-globin polypeptides, even without nuclease treatment, but retains full capacity to be stimulated by exogenous mRNA.

Impact of intravenous oxygen therapy on the expression of reticulocyte-type 15-lipoxygenase in human volunteers.

Intravenous oxygen infusion is used in complementary medicine to fight inflammatory disorders and repeated application of this therapeutic method leads to an increase in eosinophilic granulocytes in the peripheral blood. Since this subset of human peripheral leukocytes are known to express large amounts of the reticulocyte-type 15-lipoxygenase (15-lipoxygenase 1), which was suggested to exhibit anti-inflammatory activities, we profiled expression of this enzyme in the peripheral blood during the time course of typical oxygen infusion therapy. For this purpose seven volunteers were treated with intravenous infusion of oxygen gas for 4 weeks and the time-course of 15-lipoxygenase expression as well as the eosinophil count were monitored during and after the treatment interval. We found that 15-lipoxygenase 1 expression and the eosinophil count were significantly increased during the treatment period but returned to normal after the therapy was stopped. There was a striking correlation between the relative number of 15-lipoxygenase transcripts and the eosinophil counts suggesting eosinophils as major source of 15-lipoxygenase 1 expression. Since 15-lipoxygenase has been implicated in the resolving phase of acute inflammatory diseases the anti-inflammatory effects of intravenous oxygen infusion may be explained at least in part by our experimental findings.

Impaired polymorphonuclear leukocyte 15-lipoxygenase activity in juvenile and rapidly progressive periodontitis.

15-lipoxygenase activity was investigated in sonicated polymorphonuclear leukocytes (PMNLs) from patients with juvenile and rapidly progressive periodontitis and adult periodontitis. The group with juvenile and rapidly progressive periodontitis had 17 patients (6 male, 11 female, mean age 27.4 years), and the age matched control group had 18 normal individuals (11 male, 7 female, mean age 26.3 years). The group with adult periodontitis had 14 patients with 9 male, 5 female, mean age 45.2 years and the age-matched control group had 6 normal subjects with 5 male, 1 female, mean age 43.7 years. 15-hydroxyeicosa-tetraenoic acid (15-HETE) synthesized in the group with juvenile and rapidly progressive periodontitis was 0.219 +/- 0.102 ng/mg protein (mean +/- S.D.), while it was 0.410 +/- 0.138 ng/mg protein in the age-matched control group. There was a significant difference between the two groups. The group with adult periodontitis produced 0.358 +/- 0.124 ng/mg protein and the age matched control group produced 0.448 +/- 0.176 ng/mg protein (no significant difference). These results are relevant to reports that PMNLs of patients with juvenile and rapidly progressive periodontitis have abnormal functions, while those of patients with adult periodontitis are normal.

Transient experimental anemia in cholesterol-fed rabbits induces systemic overexpression of the reticulocyte-type 15-lipoxygenase and protects from aortic lipid deposition.

Oxidative modification of low-density lipoprotein has been implicated in atherogenesis and the lipid peroxidizing enzyme 12/15-lipoxygenase (12/15-LOX) was suggested to be involved. For this study, we induced a strong and long-lasting systemic overexpression of the 15-LOX, in female New Zealand White rabbits by transient experimental anemia. After the hematopoietic parameters had returned to normal, these animals and age-matched controls were fed a lipid-rich Western-type diet for 10 weeks. Analyzing the lipid deposition in the aortic wall, we found that the 15-LOX overexpressing rabbits deposited significantly (P<0.01) less cholesteryl linoleate in the thoracic aorta than the corresponding controls. Similar results were obtained when free cholesterol and cholesteryl oleate were quantified. However, in the aortic arch where lipid deposition was much more severe a similar trend was observed, but the effects were not significant any more. Comparative determination (lipoxygenase overexpressing vs. control animals) of various plasma parameters as well as histological inspections of major organs did not reveal any indications for major organ malfunction. These data suggest that transient experimental anemia, which is accompanied by a long-lasting overexpression of the reticulocyte-type 15-LOX protects cholesterol-fed rabbits from lipid deposition in the aortic wall.

Rapid purification of rabbit reticulocyte lipoxygenase for electron paramagnetic spectroscopy characterization of the non-heme iron.

An efficient three-step purification technique has been developed for the reticulocyte 15-lipoxygenase from rabbit. Ammonium sulfate fractionated reticulocyte lysate was purified by size exclusion chromatography and preparative scale isoelectric focusing. The entire procedure was complete in less than eight hours and was carried out in batches which typically yielded 10 mg of purified enzyme. The identity and purity of the enzyme were evaluated by N-terminal sequencing, sodium dodecylsulfate polyacrylamide gel electrophoresis and specific activity determinations. The enzyme contained approximately one g-atom iron per mole of protein. The iron was present in an electron paramagnetic spectroscopy (EPR) silent, presumably high spin iron(II), form in the isolated enzyme. Treatment with one equivalent of 13-hydroperoxy-9(Z),11(E)-octadecadienoic acid resulted in the appearance of an EPR signal around g6.

Regulation of cellular 15-lipoxygenase activity on pretranslational, translational, and posttranslational levels.

In mammalian cells, enzymatic lipid peroxidation catalyzed by 12/15-lipoxygenases is regulated by pretranslational, translational, and posttranslational processes. In rabbits, rats, and mice induction of experimental anemia leads to a systemic up-regulation of 12/15-lipoxygenases expression. In addition, interleukins-4 and -13 were identified as strong up-regulators of this enzyme in human and murine monocyte/macrophages and in the lung carcinoma cell line A549, and the interleukin-4(13) cell surface receptor as well as the signal transducer and activator of transcription 6 (STATG) appears to be involved in the signal transduction cascade. On the level of translation, 15-lipoxygenase synthesis is blocked by the binding of regulatory proteins to a characteristic guanine-cytosine-rich repetitive element in the 3'-untranslated region of the rabbit 15-lipoxygenase mRNA, and the formation of such 15-lipoxygenase mRNA/protein complexes was identified as molecular reason for the translational inactivity of the 15-lipoxygenase mRNA in immature red blood cells. However, proteolytic breakdown of the regulatory proteins which were recently identified as hnRNP K and hnRNP E1 overcomes translational inhibition during later stages of reticulocyte maturation. For maximal intracellular activity, 12/15-lipoxygenases require a rise in cytosolic calcium concentration inducing a translocation of the enzyme from the cytosol to cellular membranes as well as small amounts of preformed hydroperoxides which act as essential activators of the enzymes. 12/15-Lipoxygenases undergo irreversible suicide inactivation during fatty acid oxygenation, and this process may be considered an element of down-regulation of enzyme activity. Suicide inactivation and proteolytic breakdown may contribute to the disappearance of functional 12/15-lipoxygenase at later stages of erythropoiesis.

Enhancement of the HIF-1α/15-LO/15-HETE axis promotes hypoxia-induced endothelial proliferation in preeclamptic pregnancy.

Preeclampsia (PE) is an extremely serious condition in pregnant women and the leading cause of maternal and fetal morbidity and mortality. Despite active research, the etiological factors of this disorder remain elusive. The increased release of 15-hydroxyeicosatetraenoic acid (15-HETE) in the placenta of preeclamptic patients has been studied, but its exact role in PE pathogenesis remains unknown. Mounting evidence shows that PE is associated with placental hypoxia, impaired placental angiogenesis, and endothelial dysfunction. In this study, we confirmed the upregulated expression of hypoxia-inducible factor 1α (HIF-1α) and 15-lipoxygenase-1/2 (15-LO-1/2) in patients with PE. Production of the arachidonic acid metabolite, 15-HETE, also increased in the preeclamptic placenta, which suggests enhanced activation of the HIF-1α-15-LO-15-HETE axis. Furthermore, this study is the first to show that the umbilical cord of preeclamptic women contains significantly higher serum concentrations of 15-HETE than that of healthy pregnant women. The results also show that expression of 15-LO-1/2 is upregulated in both human umbilical vein endothelial cells (HUVECs) collected from preeclamptic women and in those cultured under hypoxic conditions. Exogenous 15-HETE promotes the migration of HUVECs and in vitro tube formation and promotes cell cycle progression from the G0/G1 phase to the G2/M + S phase, whereas the 15-LO inhibitor, NDGA, suppresses these effects. The HIF-1α/15-LO/15-HETE pathway is therefore significantly associated within the pathology of PE.