Diabetes-Induced Oxidative Stress Is Mediated by Ca2+-Independent Phospholipase A2 in Neutrophils
| العنوان: | Diabetes-Induced Oxidative Stress Is Mediated by Ca2+-Independent Phospholipase A2 in Neutrophils |
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| المؤلفون: | Alpdogan Kantarci, Thomas E. Van Dyke, Motohiko Yagi, Hatice Hasturk, Tomoyuki Iwata, Gabrielle Fredman, Hongsheng Liu, Kazuhiro Omori, Oya Türkoğlu, Srinivas Ayilavarapu |
| المصدر: | The Journal of Immunology. 184:1507-1515 |
| بيانات النشر: | The American Association of Immunologists, 2010. |
| سنة النشر: | 2010 |
| مصطلحات موضوعية: | Adult, Male, Neutrophils, Immunology, Phosphatidate Phosphatase, HL-60 Cells, Article, Group VI Phospholipases A2, chemistry.chemical_compound, Phospholipase A2, Downregulation and upregulation, Superoxides, Humans, Immunology and Allergy, Protein Kinase C, Protein kinase C, NADPH oxidase, biology, Superoxide, Phosphatidic acid, Middle Aged, Molecular biology, Up-Regulation, Oxidative Stress, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, chemistry, Biochemistry, Gene Targeting, biology.protein, Calcium, Female, Arachidonic acid, Signal transduction, Signal Transduction |
| الوصف: | Neutrophils from people with poorly controlled diabetes present a primed phenotype and secrete excessive superoxide. Phospholipase A2 (PLA2)-derived arachidonic acid (AA) activates the assembly of NADPH oxidase to generate superoxide anion. There is a gap in the current literature regarding which PLA2 isoform regulates NADPH oxidase activation. The aim of this study was to identify the PLA2 isoform involved in the regulation of superoxide generation in neutrophils and investigate if PLA2 mediates priming in response to pathologic hyperglycemia. Neutrophils were isolated from people with diabetes mellitus and healthy controls, and HL60 neutrophil-like cells were grown in hyperglycemic conditions. Incubating neutrophils with the Ca2+-independent PLA2 (iPLA2) inhibitor bromoenol lactone (BEL) completely suppressed fMLP-induced generation of superoxide. The nonspecific actions of BEL on phosphatidic acid phosphohydrolase-1, p47phox phosphorylation, and apoptosis were ruled out by specific assays. Small interfering RNA knockdown of iPLA2 inhibited superoxide generation by neutrophils. Neutrophils from people with poorly controlled diabetes and in vitro incubation of neutrophils with high glucose and the receptor for advanced glycation end products ligand S100B greatly enhanced superoxide generation compared with controls, and this was significantly inhibited by BEL. A modified iPLA2 assay, Western blotting, and PCR confirmed that there was increased iPLA2 activity and expression in neutrophils from people with diabetes. AA (10 μM) partly rescued the inhibition of superoxide generation mediated by BEL, confirming that NADPH oxidase activity is, in part, regulated by AA. This study provides evidence for the role of iPLA2 in enhanced superoxide generation in neutrophils from people with diabetes mellitus and presents an alternate pathway independent of protein kinase C and phosphatidic acid phosphohydrolase-1 hydrolase signaling. |
| تدمد: | 1550-6606 0022-1767 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5f7cdd40d86dbb76908a1cd9125fea74Test https://doi.org/10.4049/jimmunol.0901219Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....5f7cdd40d86dbb76908a1cd9125fea74 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15506606 00221767 |
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