title: Chronic nitric oxide deprivation induces an adaptive antioxidant status in human endothelial cells.
abstract: In a previous work, we showed an increased cell motility due to the accumulation and transcriptional activation of the Hypoxia Inducible Factor-1α (HIF-1α) and a reduced mitochondrial energy production in an in vitro model of endothelial dysfunction (ED) represented by human endothelial cells (ECs) chronically deprived of nitric oxide (NO) by L-NAME treatment. In the present study, in the attempt to unravel the pathway(s) linking NO deficiency to HIF-1α accumulation and activation, we focused our attention on Reactive Oxygen Species (ROS). We found that ROS were partially involved in HIF-1α stabilization, but not in the pro-migratory phenotype. Regarding mitochondrial dysfunction, it did not require neither ROS generation nor HIF-1α activity, and was not due to autophagy. Very interestingly, while acute treatment with L-NAME induced a transient increase in ROS formation, chronic NO deprivation by long term L-NAME exposure drastically reduced cellular ROS content giving rise to an antioxidant environment characterized by an increase in superoxide dismutase-2 (SOD-2) expression and activity, and by nuclear accumulation of the transcription factor NF-E2-related factor-2 (Nrf2). These results might have important implications for our understanding of the consequences of NO deprivation in endothelium behavior and in the onset of cardiovascular diseases.
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Via Vanvitelli 32, 20129 Milano, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Cattaneo
authors.forename: Elisa
authors.initials: E
authors.lastname: Cappellini
authors.forename: Maurizio
authors.initials: M
authors.lastname: Ragni
authors.forename: Lorenza
authors.initials: L
authors.lastname: Tacchini
authors.forename: Diletta
authors.initials: D
authors.lastname: Scaccabarozzi
authors.forename: Enzo
authors.initials: E
authors.lastname: Nisoli
authors.forename: Lucia Maria
authors.initials: LM
authors.lastname: Vicentini
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects*; D000975:Antioxidants / Q000378:metabolism; D002465:Cell Movement; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D000099156:Superoxide Dismutase 2
chemical_list: D000975:Antioxidants; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051267:NF-E2-Related Factor 2; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C497442:HIF1A protein, human; C495635:NFE2L2 protein, human; C496319:NOS2 protein, human
keywords: Endothelium; Hypoxia Inducible Factor-1; NF-E2-related factor-2; Nitric oxide; Reactive Oxygen Species