High glucose inhibits insulin-stimulated nitric oxide production without reducing endothelial nitric-oxide synthase Ser1177 phosphorylation in human aortic endothelial cells
| Autor: | Ian P. Salt, John M. C. Connell, Valerie A. Morrow, Fiona M. Brandie, John R. Petrie |
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| Rok vydání: | 2003 |
| Předmět: |
medicine.medical_specialty
Endothelium Insulin Receptor Substrate Proteins Nitric Oxide Synthase Type III medicine.medical_treatment Ubiquitin-Protein Ligases Protein Serine-Threonine Kinases Nitric Oxide Biochemistry Phosphatidylinositol 3-Kinases Phosphoserine Enos Internal medicine Proto-Oncogene Proteins medicine Humans Insulin Proto-Oncogene Proteins c-cbl Phosphorylation Molecular Biology Protein kinase B Aorta Cells Cultured biology Chemistry Intracellular Signaling Peptides and Proteins Cell Biology biology.organism_classification Phosphoproteins Insulin receptor Cytoskeletal Proteins medicine.anatomical_structure Endocrinology Glucose biology.protein Endothelium Vascular Nitric Oxide Synthase Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | The Journal of biological chemistry. 278(21) |
| ISSN: | 0021-9258 |
| Popis: | Recent studies have indicated that insulin activates endothelial nitric-oxide synthase (eNOS) by protein kinase B (PKB)-mediated phosphorylation at Ser1177 in endothelial cells. Because hyperglycemia contributes to endothelial dysfunction and decreased NO availability in types 1 and 2 diabetes mellitus, we have studied the effects of high glucose (25 mM, 48 h) on insulin signaling pathways that regulate NO production in human aortic endothelial cells. High glucose inhibited insulin-stimulated NO synthesis but was without effect on NO synthesis stimulated by increasing intracellular Ca2+ concentration. This was accompanied by reduced expression of IRS-2 and attenuated insulin-stimulated recruitment of PI3K to IRS-1 and IRS-2, yet insulin-stimulated PKB activity and phosphorylation of eNOS at Ser1177 were unaffected. Inhibition of insulin-stimulated NO synthesis by high glucose was unaffected by an inhibitor of PKC. Furthermore, high glucose down-regulated the expression of CAP and Cbl, and insulin-stimulated Cbl phosphorylation, components of an insulin signaling cascade previously characterized in adipocytes. These data suggest that high glucose specifically inhibits insulin-stimulated NO synthesis and down-regulates some aspects of insulin signaling, including the CAP-Cbl signaling pathway, yet this is not a result of reduced PKB-mediated eNOS phosphorylation at Ser1177. Therefore, we propose that phosphorylation of eNOS at Ser1177 is not sufficient to stimulate NO production in cells cultured at 25 mM glucose. |
| Databáze: | OpenAIRE |
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