title: TNF-alpha inhibits flow and insulin signaling leading to NO production in aortic endothelial cells.
abstract: Endothelial cells release nitric oxide (NO) acutely in response to increased "flow" or fluid shear stress (FSS), and the increase in NO production is correlated with enhanced phosphorylation and activation of endothelial nitric oxide synthase (eNOS). Both vascular endothelial growth factor and FSS activate endothelial protein kinase B (PKB) by way of incompletely understood pathway(s), and, in turn, PKB phosphorylates eNOS at Ser-1179, causing its activation. In this study, we found that either FSS or insulin stimulated insulin receptor substrate-1 (IRS-1) tyrosine and serine phosphorylation and increased IRS-1-associated phosphatidylinositol 3-kinase activity, phosphorylation of PKB Ser-473, phosphorylation of eNOS Ser-1179, and NO production. Brief pretreatment of bovine aortic endothelial cells with tumor necrosis factor-alpha (TNF-alpha) inhibited the above described FSS- or insulin-stimulated protein phosphorylation events and almost totally inhibited FSS- or insulin-stimulated NO production. These data indicate that FSS and insulin regulate eNOS phosphorylation and NO production by overlapping mechanisms. This study suggests one potential mechanism for the development of endothelial dysfunction in disease states with alterations in insulin regulation and increased TNF-alpha levels.
authors: Department of Medicine, Division of Cardiology, Harborview Medical Center, University of Washington, Seattle, Washington 98104, USA. fkim@u.washington.edu
authors: F
authors: F
authors: Kim
authors: B
authors: B
authors: Gallis
authors: M A
authors: MA
authors: Corson
mesh_terms: D000818:Animals; D001011:Aorta; D002417:Cattle; D002478:Cells, Cultured; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D004789:Enzyme Activation; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D007700:Kinetics; D008222:Lymphokines / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D010769:Phosphothreonine / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013314:Stress, Mechanical; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D008222:Lymphokines; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D010769:Phosphothreonine; D010768:Phosphoserine; D019000:Phosphotyrosine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt