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Arachidonate 15 Lipoxygenase

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Lillemor Mattsson Hultén – One of the best experts on this subject based on the ideXlab platform.

  • Hypoxic cardiac fibroblasts from failing human hearts decrease cardiomyocyte beating frequency in an ALOX15 dependent manner
    , 2018
    Co-Authors: Mikael Sandstedt, Annika Lundqvist, Joakim Sandstedt, Victoria Rotter Sopasakis, Kristina Vukusic, Anders Oldfors, Göran Dellgren, Lillemor Mattsson Hultén

    Abstract:

    A common denominator for patients with heart failure is the correlation between elevated serum levels of proinflammatory cytokines and adverse clinical outcomes. Furthermore, Lipoxygenase-induced inflammation is reportedly involved in the pathology of heart failure. Cardiac fibroblasts, which are abundant in cardiac tissue, are known to be activated by inflammation. We previously showed high expression of the Lipoxygenase Arachidonate 15 Lipoxygenase (ALOX15), which catalyzes the conversion of arachidonic acid to 15-hydroxy eicosatetraenoic acid (15-HETE), in ischemic cardiac tissue. The exact roles of ALOX15 and 15-HETE in the pathogenesis of heart failure are however unknown. Biopsies were collected from all chambers of explanted failing human hearts from heart transplantation patients, as well as from the left ventricles from organ donors not suffering from chronic heart failure. Biopsies from the left ventricles underwent quantitative immunohistochemical analysis for ALOX15/B. Gene expression of ALOX enzymes, as well as 15-HETE levels, were examined in cardiac fibroblasts which had been cultured in either hypoxic or normoxic conditions after isolation from failing hearts. After the addition of fibroblast supernatants to human induced pluripotent stem cell-derived cardiomyocytes, intracellular calcium concentrations were measured to examine the effect of paracrine signaling on cardiomyocyte beating frequency. While ALOX15 and ALOX15B were expressed throughout failing hearts as well as in hearts from organ donors, ALOX15 was expressed at significantly higher levels in donor hearts. Hypoxia resulted in a significant increase in gene and protein expression of ALOX15 and ALOX15B in fibroblasts isolated from the different chambers of failing hearts. Finally, preconditioned medium from hypoxic fibroblasts decreased the beating frequency of human cardiomyocytes derived from induced pluripotent stem cells in an ALOX15-dependent manner. In summary, our results demonstrate that ALOX15/B signaling by hypoxic cardiac fibroblasts may play an important role in ischemic cardiomyopathy, by decreasing cardiomyocyte beating frequency.

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  • The Arachidonate 15Lipoxygenase Enzyme Product 15-HETE Is Present in Heart Tissue from Patients with Ischemic Heart Disease and Enhances Clot Formation
    , 2016
    Co-Authors: Annika Lundqvist, Anders Jeppsson, Mikael Sandstedt, Joakim Sandstedt, Ruth Wickelgren, Göran I. Hansson, Lillemor Mattsson Hultén

    Abstract:

    Ischemic heart disease is a major cause of death and morbidity and the search for novel therapeutic targets is still required. We have previously shown that the enzyme Arachidonate 15 Lipoxygenase (ALOX15), which catalyzes the conversion of arachidonic acid to 15-hydroxy eicosatetraenoic acid (15-HETE), is highly expressed in ischemic heart tissue, but its role in the pathogenesis of ischemic heart disease is unclear. Here we showed that expression of ALOX15, but not ALOX12 or ALOX15B, was increased in ischemic versus non-ischemic human heart biopsy samples. A similar ALOX expression pattern was found in hypoxic human cardiomyocytes and cardiac endothelial cells. We also showed that levels of 15-HETE were significantly higher in ischemic versus non-ischemic human heart biopsy samples and showed a tendency to increase in serum from the patients with ischemic heart disease. Moreover, hypoxia increased the production of 15-HETE levels from human cardiomyocytes and cardiac endothelial cells. The hypoxia-induced increase in 15-HETE levels from human cardiomyocytes was inhibited by the ALOX15 inhibitor baicalein. Finally, by using intrinsic rotational thromboelastometry, we showed that human whole blood clotted faster in the presence of 15-HETE. In summary, we propose that increased ALOX15 expression in heart tissue under ischemic conditions may lead to increased production of 15-HETE, potentially contributing to thrombosis.

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  • Arachidonate 15Lipoxygenase Enzyme Products Increase Platelet Aggregation and Thrombin Generation
    , 2014
    Co-Authors: Carolina Vijil, Cecilia Hermansson, Anders Jeppsson, Göran Bergström, Lillemor Mattsson Hultén

    Abstract:

    Atherosclerotic cardiovascular diseases are the leading causes of morbidity and mortality worldwide. We have previously shown that Arachidonate 15Lipoxygenase B (ALOX15B) is highly expressed in atherosclerotic carotid plaques, and elucidation of mechanisms downstream of activated Lipoxygenases may be relevant to our understanding of the genesis of atherosclerotic diseases. We examined 120 carotid plaques from patients with symptomatic carotid artery stenosis and showed that the extent of ALOX15B staining was significantly increased in carotid plaques with thrombosis. Impedance aggregometry analyses showed that the ALOX15B enzyme products 15-HETE and 15-HPETE increased platelet aggregation. By using a calibrated automatic thrombin assay, we showed that the ALOX15B products also increased both peak levels of thrombin and the total endogenous thrombin potential. Moreover, platelet aggregation was increased by addition of cell lysates from ischemic human macrophages, whereas platelet aggregation was reduced after knockdown of ALOX15B in human macrophages. Our data show that ALOX15B expression in human carotid plaques is associated with thrombus formation and that enzyme products of ALOX15B increase platelet aggregation and thrombin generation. We therefore propose that activated ALOX15B in macrophages may play a role in the induction of atherothrombotic events by increasing platelet aggregation and thrombin generation.

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Bengt Samuelsson – One of the best experts on this subject based on the ideXlab platform.

  • Purification of two forms of Arachidonate 15Lipoxygenase from human leukocytes
    European journal of biochemistry, 1991
    Co-Authors: Takashi Izumi, Olof Rådmark, Hans Jörnvall, Bengt Samuelsson

    Abstract:

    Two different proteins with Arachidonate 15Lipoxygenase activity have been purified to near homogeneity from human leukocytes. Both have the same molecular mass (74 kDa) on SDS/PAGE and appear to be equally active with three different fatty acid substrates. The N-terminal amino acid sequences of both forms were identical to the sequence of human reticulocyte 15Lipoxygenase [Sigal, E., Criak, C. S., Highland, E., Grunberger, D., Costello, L. L., Dixon, R. A. F. & Nadel, J. A. (1988) Biochem. Biophys. Res. Commun. 157 457–464]. The two forms of 15Lipoxygenase could be clearly separated by cation-exchange chromatography. Of particular interest, the relative amounts of the two forms differed markedly between leukocytes obtained from donors and leukocyltes from an individual with eosinophilia.

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  • purification of two forms of Arachidonate 15 Lipoxygenase from human leukocytes
    FEBS Journal, 1991
    Co-Authors: Takashi Izumi, Olof Rådmark, Hans Jörnvall, Bengt Samuelsson

    Abstract:

    Two different proteins with Arachidonate 15Lipoxygenase activity have been purified to near homogeneity from human leukocytes. Both have the same molecular mass (74 kDa) on SDS/PAGE and appear to be equally active with three different fatty acid substrates. The N-terminal amino acid sequences of both forms were identical to the sequence of human reticulocyte 15Lipoxygenase [Sigal, E., Criak, C. S., Highland, E., Grunberger, D., Costello, L. L., Dixon, R. A. F. & Nadel, J. A. (1988) Biochem. Biophys. Res. Commun. 157 457–464]. The two forms of 15Lipoxygenase could be clearly separated by cation-exchange chromatography. Of particular interest, the relative amounts of the two forms differed markedly between leukocytes obtained from donors and leukocyltes from an individual with eosinophilia.

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Luo Zhang – One of the best experts on this subject based on the ideXlab platform.

  • Predictive significance of Arachidonate 15Lipoxygenase for eosinophilic chronic rhinosinusitis with nasal polyps.
    Allergy asthma and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology, 2020
    Co-Authors: Zhuoping Liang, Yan Bing, Chang Liu, Ruyu Tan, Chengshuo Wang, Luo Zhang

    Abstract:

    Background Eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP) exhibits a poorer outcome compared with non-eosinophilic chronic rhinosinusitis with nasal polyps (nonECRSwNP), so it is significant to identify effective markers to differentiate ECRSwNP in guiding the treatment strategies of these patients. Although Arachidonate 15Lipoxygenase (ALOX15) is positioned as a marker of eosinophilic inflammation, its study in differentiating ECRSwNP has not been reported. The aim of this study is to assess the potential of ALOX15 in distinguishing and predicting ECRSwNP. Methods Forty-eight patients with chronic rhinosinusitis with nasal polyps (CRSwNP), including 30 ECRSwNP and 18 nonECRSwNP patients, were enrolled. ALOX15 mRNA level was determined in polyps by real-time polymerase chain reaction (RT-PCR). The patients’ baseline characteristics were evaluated and analyzed for correlations with ALOX15. Receiver operating characteristic (ROC) curve was used to assess the predictive significance of the potential predictors for ECRSwNP. Results ALOX15 mRNA level was significantly higher in ECRSwNP patients than in nonECRSwNP patients (P 

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  • Predictive significance of Arachidonate 15Lipoxygenase for eosinophilic chronic rhinosinusitis with nasal polyps
    , 2020
    Co-Authors: Zhuoping Liang, Chang Liu, Ruyu Tan, Chengshuo Wang, Bing Yan, Luo Zhang

    Abstract:

    Abstract
    Background: Eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP) exhibits a poorer outcome compared with non-eosinophilic chronic rhinosinusitis with nasal polyps (nonECRSwNP), so it is significant to identify effective markers to differentiate ECRSwNP in guiding the treatment strategies of these patients. Although Arachidonate 15Lipoxygenase (ALOX15) is positioned as a marker of eosinophilic inflammation, its study in differentiating ECRSwNP has not been reported. The aim of this study is to assess the potential of ALOX15 in distinguishing and predicting ECRSwNP. Methods: Forty-eight patients with chronic rhinosinusitis with nasal polyps (CRSwNP), including 30 ECRSwNP and 18 nonECRSwNP patients, were enrolled. ALOX15 mRNA level was determined in polyps by real-time polymerase chain reaction (RT-PCR). The patients’ baseline characteristics were evaluated and analyzed for correlations with ALOX15. Receiver operating characteristic (ROC) curve was used to assess the predictive significance of the potential predictors for ECRSwNP.Results: ALOX15 mRNA level was significantly higher in ECRSwNP patients than in nonECRSwNP patients (P < 0.001). ALOX15 mRNA was significantly correlated with tissue and blood eosinophil percentages (r = 0.565, P < 0.001 and r = 0.395, P = 0.006), olfaction scores (r = 0.400, P = 0.005), total visual analogue scale (VAS) symptom scores (r = 0.383, P = 0.007), ethmoid/maxillary sinus (E/M) ratio (r = 0.463, P = 0.001), and endoscopy scores (r = 0.409, P = 0.004). Logistic regression analysis showed ALOX15 mRNA level and percentage of blood eosinophils to be predictive factors for ECRSwNP (P = 0.004 and P = 0.036, respectively). ROC curve indicated ALOX15 to have high predictive accuracy for ECRSwNP (area under the curve (AUC) = 0.909), which was further improved by combination of ALOX15 with percentage of blood eosinophils (AUC = 0.933). Conclusions: The relative ALOX15 mRNA level alone or in combination with blood eosinophils might be a reliable biomarker for predicting a diagnosis of ECRSwNP.

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  • Inhibition of Arachidonate 15Lipoxygenase reduces the epithelial-mesenchymal transition in eosinophilic chronic rhinosinusitis with nasal polyps.
    International forum of allergy & rhinology, 2018
    Co-Authors: Yan Bing, Chengshuo Wang, Yang Wang, Luo Zhang

    Abstract:

    BACKGROUND The epithelial-mesenchymal transition (EMT) is a distinguishing characteristic of chronic rhinosinusitis with nasal polyps (CRSwNP). The underlying mechanism remains largely unknown. Arachidonate 15Lipoxygenase (ALOX15), an enzyme involved in arachidonic acid metabolism, has been reported to cause airway epithelial injury and thus may further promote the EMT. The aim of this study was to evaluate the role of ALOX15 during the EMT process in CRSwNP. METHODS A total of 54 samples were obtained, including 10 from healthy control, 16 from non-eosinophilic CRSwNP, and 28 from eosinophilic CRSwNP. Hematoxylin and eosin staining was performed to determine the basement membrane (BM) thickness. The concentration of molecules mediating remodeling was assayed by Luminex. The messenger RNA (mRNA) and protein levels of target genes were measured by quantitative real-time polymerase chain reaction (PCR) and Western blotting. RESULTS EMT was enhanced in eosinophilic CRSwNP compared with the healthy controls and non-eosinophilic CRSwNP infiltrated with lymphocytes and/or plasma cells. The expression pattern of molecules related to remodeling, including matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinases (TIMPs), and transforming growth factor β (TGF-β) family members, differed between the subtypes of CRSwNP. The mRNA level of ALOX15 was correlated with the BM thickness and MMP-1 and TGF-β3 expression. The inhibition of ALOX15 by PD146176 could induce claudin-1, claudin-4, claudin-7, zonula occludens (ZO)-1, ZO-2, E-Cadherin, TIMP-1, and TIMP-3 expressions and reduce the levels of MMP-1 and N-Cadherin in epithelial cells acquired from eosinophilic CRSwNP patients. CONCLUSION The specific inhibition of ALOX15 could attenuate the EMT, which may provide an alternative method for the treatment of CRSwNP.

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