1. Trans-arachidonic acids generated during nitrative stress induce a thrombospondin-1-dependent microvascular degeneration
- Author
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Gregor Andelfinger, Chantal J. Boisvert, Elsa Kermorvant-Duchemin, Sonia Brault, Huy Ong, J Russel Falck, Pedro D'Orléans-Juste, Florian Sennlaub, Stéphane Germain, Pierre Hardy, Michael Balazy, Amna Kooli, Fernand Gobeil, Tang Zhu, Kavita Jain, Mirna Sirinyan, Sylvain Chemtob, Department of Pediatrics, Ophthalmology and Pharmacology, Hôpital Sainte-Justine, Physiopathologie des Maladies Oculaires : Innovations Therapeutiques, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Pharmacology and Therapeutics [Montréal], McGill University = Université McGill [Montréal, Canada], Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculty of Pharmacy [Montréal, QC, Canada], Université de Montréal (UdeM), Department of Pharmacology, Université de Sherbrooke (UdeS), New York Medical College (NYMC), Department of Biochemistry, The University of Texas Health Science Center at Houston (UTHealth), Sennlaub, Florian, and CHU Sainte Justine [Montréal]
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MESH: Oxidation-Reduction ,MESH: Nitroarginine ,Sus scrofa ,Tetrazolium Salts ,Apoptosis ,MESH: Rats, Sprague-Dawley ,MESH: Animals, Newborn ,Neovascularization ,Rats, Sprague-Dawley ,Thrombospondin 1 ,chemistry.chemical_compound ,0302 clinical medicine ,MESH: Microcirculation ,MESH: Animals ,Cells, Cultured ,MESH: Glutathione ,0303 health sciences ,MESH: Oxidative Stress ,Reverse Transcriptase Polymerase Chain Reaction ,MESH: Retina ,General Medicine ,3. Good health ,Cell biology ,Biochemistry ,MESH: Metalloporphyrins ,MESH: Isoenzymes ,Arachidonic acid ,MESH: Nitric Oxide Synthase ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,medicine.symptom ,MESH: Oxygen ,MESH: Rats ,Cell Survival ,Blotting, Western ,MESH: Malondialdehyde ,Ischemia ,Neovascularization, Physiologic ,Arachidonic Acids ,Biology ,Nitric Oxide ,General Biochemistry, Genetics and Molecular Biology ,Article ,Nitric oxide ,03 medical and health sciences ,Downregulation and upregulation ,In vivo ,medicine ,In Situ Nick-End Labeling ,Animals ,[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,030304 developmental biology ,DNA Primers ,MESH: Antioxidants ,Endothelial Cells ,Retinal Vessels ,medicine.disease ,Rats ,Thiazoles ,chemistry ,Gene Expression Regulation ,MESH: Nitric Oxide ,030217 neurology & neurosurgery ,Ex vivo ,Diabetic Angiopathies - Abstract
E K-D and F S contributed equally to this work; Nitrative stress has an important role in microvascular degeneration leading to ischemia in conditions such as diabetic retinopathy and retinopathy of prematurity. Thus far, mediators of nitrative stress have been poorly characterized. We recently described that trans-arachidonic acids are major products of NO(2)(*)-mediated isomerization of arachidonic acid within the cell membrane, but their biological relevance is unknown. Here we show that trans-arachidonic acids are generated in a model of retinal microangiopathy in vivo in a NO(*)-dependent manner. They induce a selective time- and concentration-dependent apoptosis of microvascular endothelial cells in vitro, and result in retinal microvascular degeneration ex vivo and in vivo. These effects are mediated by an upregulation of the antiangiogenic factor thrombospondin-1, independently of classical arachidonic acid metabolism. Our findings provide new insight into the molecular mechanisms of nitrative stress in microvascular injury and suggest new therapeutic avenues in the management of disorders involving nitrative stress, such as ischemic retinopathies and encephalopathies.
- Published
- 2005
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