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      The Arachidonate 15-Lipoxygenase Enzyme Product 15-HETE Is Present in Heart Tissue from Patients with Ischemic Heart Disease and Enhances Clot Formation

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          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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          Most cited references20

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          Mammalian lipoxygenases and their biological relevance.

          Lipoxygenases (LOXs) form a heterogeneous class of lipid peroxidizing enzymes, which have been implicated not only in cell proliferation and differentiation but also in the pathogenesis of various diseases with major public health relevance. As other fatty acid dioxygenases LOXs oxidize polyunsaturated fatty acids to their corresponding hydroperoxy derivatives, which are further transformed to bioactive lipid mediators (eicosanoids and related substances). On the other hand, lipoxygenases are key players in the regulation of the cellular redox homeostasis, which is an important element in gene expression regulation. Although the first mammalian lipoxygenases were discovered 40 years ago and although the enzymes have been well characterized with respect to their structural and functional properties the biological roles of the different lipoxygenase isoforms are not completely understood. This review is aimed at summarizing the current knowledge on the physiological roles of different mammalian LOX-isoforms and their patho-physiological function in inflammatory, metabolic, hyperproliferative, neurodegenerative and infectious disorders. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance".
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            Aspirin "resistance" and risk of cardiovascular morbidity: systematic review and meta-analysis.

            To determine if there is a relation between aspirin "resistance" and clinical outcomes in patients with cardiovascular disease. Systematic review and meta-analysis. Electronic literature search without language restrictions of four databases and hand search of bibliographies for other relevant articles. Inclusion criteria included a test for platelet responsiveness and clinical outcomes. Aspirin resistance was assessed, using a variety of platelet function assays. 20 studies totalling 2930 patients with cardiovascular disease were identified. Most studies used aspirin regimens, ranging from 75-325 mg daily, and six studies included adjunct antiplatelet therapy. Compliance was confirmed directly in 14 studies and by telephone or interviews in three. Information was insufficient to assess compliance in three studies. Overall, 810 patients (28%) were classified as aspirin resistant. A cardiovascular related event occurred in 41% of patients (odds ratio 3.85, 95% confidence interval 3.08 to 4.80), death in 5.7% (5.99, 2.28 to 15.72), and an acute coronary syndrome in 39.4% (4.06, 2.96 to 5.56). Aspirin resistant patients did not benefit from other antiplatelet treatment. Patients who are resistant to aspirin are at a greater risk of clinically important cardiovascular morbidity long term than patients who are sensitive to aspirin.
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              Cardiomyopathy of the aging human heart. Myocyte loss and reactive cellular hypertrophy.

              To determine the effects of aging on the human myocardium, 67 hearts were obtained from individuals who died from causes other than cardiovascular disease. The age interval examined was 17-90 years. Regression analysis demonstrated that the aging process was characterized by a loss of 38 million and 14 million myocyte nuclei/yr in the left and right ventricular myocardium, respectively. This loss in muscle mass was accompanied by a progressive increase in myocyte cell volume per nucleus in both ventricles. Left ventricular myocytes enlarged by 110 microns3/yr, whereas right ventricular myocytes increased by 118 microns3/yr, resulting in a preservation of ventricular wall thickness. However, the cellular hypertrophic response was unable to maintain normal cardiac mass. Left and right ventricular weights decreased by 0.70 and 0.21 g/yr, respectively. In conclusion, loss of cells and enlargement of the remaining myocytes may represent the structural basis for the reduced compensatory capacity of the aged heart and together may contribute to the development of myocardial dysfunction and failure in the elderly.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                23 August 2016
                2016
                : 11
                : 8
                Affiliations
                [1 ]Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg and Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden
                [2 ]Translational Sciences, AstraZeneca R&D, Mölndal, Sweden
                [3 ]Department of Cardiothoracic Surgery, Sahlgrenska University Hospital Gothenburg, Sweden and Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
                [4 ]Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
                Southern Illinois University School of Medicine, UNITED STATES
                Author notes

                Competing Interests: Göran I. Hansson was employed by the company Astra Zeneca R&D; he is now retired. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

                • Conceived and designed the experiments: AL JS AJ LMH.

                • Performed the experiments: AL MS RW GIH LMH.

                • Analyzed the data: AL MS RW GIH LMH.

                • Contributed reagents/materials/analysis tools: AL JS GIH AJ LMH.

                • Wrote the paper: AL MS JS RW GIH AJ LMH.

                Article
                PONE-D-16-00376
                10.1371/journal.pone.0161629
                4994938
                27552229
                82e7dbac-ecfa-4766-8710-b0e1f9d2a8ad
                © 2016 Lundqvist et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Figures: 3, Tables: 2, Pages: 13
                Product
                Funding
                This work was supported by the Swedish Research Council, the Swedish Heart-Lung Foundation, the Swedish Federal Government under the LUA/ALF agreement, the Emelle Foundation and the Laboratory Medicine at Sahlgrenska University Hospital Sweden.
                Categories
                Research Article
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Epithelial Cells
                Endothelial Cells
                Biology and Life Sciences
                Anatomy
                Biological Tissue
                Epithelium
                Epithelial Cells
                Endothelial Cells
                Medicine and Health Sciences
                Anatomy
                Biological Tissue
                Epithelium
                Epithelial Cells
                Endothelial Cells
                Biology and Life Sciences
                Anatomy
                Cardiovascular Anatomy
                Heart
                Medicine and Health Sciences
                Anatomy
                Cardiovascular Anatomy
                Heart
                Medicine and Health Sciences
                Vascular Medicine
                Coronary Heart Disease
                Medicine and Health Sciences
                Cardiology
                Coronary Heart Disease
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Cardiovascular Procedures
                Coronary Artery Bypass Grafting
                Biology and Life Sciences
                Genetics
                Gene Expression
                Physical Sciences
                Chemistry
                Chemical Elements
                Oxygen
                Medicine and Health Sciences
                Pulmonology
                Medical Hypoxia
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Biopsy
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

                Uncategorized
                Uncategorized

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