title: Oxidative stress is a critical mediator of the angiotensin II signal in human neutrophils: involvement of mitogen-activated protein kinase, calcineurin, and the transcription factor NF-kappaB.
abstract: Neutrophils are mobilized to the vascular wall during vessel inflammation. Published data are conflicting on phagocytic nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase activation during the hypertensive state, and the capacity of angiotensin II (Ang II) to modulate the intracellular redox status has not been analyzed in neutrophils. We here describe that Ang II highly stimulates endogenous and extracellular O2- production in these cells, consistent with the translocation to the cell membrane of the cytosolic components of NADPH oxidase, p47phox, and p67phox. The Ang II-dependent O2- production was suppressed by specific inhibitors of AT1 receptors, of the p38MAPK and ERK1/2 pathways, and of flavin oxidases. Furthermore, Ang II induced a robust phosphorylation of p38MAPK, ERK1/2, and JNK1/2 (particularly JNK2), which was hindered by inhibitors of NADPH oxidase, tyrosine kinases, and ROS scavengers. Ang II increased cytosolic Ca2+ levels-released mainly from calcium stores-enhanced the synthesis de novo and activity of calcineurin, and stimulated the DNA-binding activity of the transcription factor NF-kappaB in cultured human neutrophils. Present data demonstrate for the first time a stimulatory role of Ang II in the activation of phagocytic cells, underscore the relevant role of ROS as mediators in this process, and uncover a variety of signaling pathways by which Ang II operates in human neutrophils.
authors.affiliation: Departamento Bioquímica Médica y Biología Molecular, Universidad de Sevilla, Spain.
authors.forename: Rajaa
authors.initials: R
authors.lastname: El Bekay
authors.forename: Moisés
authors.initials: M
authors.lastname: Alvarez
authors.forename: Javier
authors.initials: J
authors.lastname: Monteseirín
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Alba
authors.forename: Pedro
authors.initials: P
authors.lastname: Chacón
authors.forename: Antonio
authors.initials: A
authors.lastname: Vega
authors.forename: José
authors.initials: J
authors.lastname: Martin-Nieto
authors.forename: Juan
authors.initials: J
authors.lastname: Jiménez
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Pintado
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Bedoya
authors.forename: Francisco
authors.initials: F
authors.lastname: Sobrino
mesh_terms: D000804:Angiotensin II / Q000502:physiology*; D057911:Angiotensin Receptor Antagonists; D019703:Calcineurin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002118:Calcium; D020013:Calcium Signaling / Q000502:physiology*; D002614:Chelating Agents / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019255:NADPH Oxidases; D016328:NF-kappa B / Q000502:physiology*; D009504:Neutrophils / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000378:metabolism; D021381:Protein Transport; D017382:Reactive Oxygen Species / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1; D016897:Respiratory Burst / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D057911:Angiotensin Receptor Antagonists; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D016328:NF-kappa B; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; C079789:neutrophil cytosol factor 67K; D000804:Angiotensin II; D004247:DNA; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D048056:Mitogen-Activated Protein Kinase 9; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019703:Calcineurin; D002118:Calcium