title: Trans-arachidonic acids generated during nitrative stress induce a thrombospondin-1-dependent microvascular degeneration.
abstract: 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.
authors.affiliation: Department of Pediatrics, Ophthalmology and Pharmacology, Research Center, Hôpital Ste-Justine, 3175 Côte de Ste-Catherine, Montréal, Québec, H3T1C5, Canada.
authors.forename: Elsa
authors.initials: E
authors.lastname: Kermorvant-Duchemin
authors.forename: Florian
authors.initials: F
authors.lastname: Sennlaub
authors.forename: Mirna
authors.initials: M
authors.lastname: Sirinyan
authors.forename: Sonia
authors.initials: S
authors.lastname: Brault
authors.forename: Gregor
authors.initials: G
authors.lastname: Andelfinger
authors.forename: Amna
authors.initials: A
authors.lastname: Kooli
authors.forename: Stéphane
authors.initials: S
authors.lastname: Germain
authors.forename: Huy
authors.initials: H
authors.lastname: Ong
authors.forename: Pedro
authors.initials: P
authors.lastname: d'Orleans-Juste
authors.forename: Fernand
authors.initials: F
authors.lastname: Gobeil
authors.forename: Tang
authors.initials: T
authors.lastname: Zhu
authors.forename: Chantal
authors.initials: C
authors.lastname: Boisvert
authors.forename: Pierre
authors.initials: P
authors.lastname: Hardy
authors.forename: Kavita
authors.initials: K
authors.lastname: Jain
authors.forename: J Russel
authors.initials: JR
authors.lastname: Falck
authors.forename: Michael
authors.initials: M
authors.lastname: Balazy
authors.forename: Sylvain
authors.initials: S
authors.lastname: Chemtob
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001095:Arachidonic Acids / Q000378:metabolism / Q000633:toxicity*; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D017931:DNA Primers; D003925:Diabetic Angiopathies / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects*; D020287:In Situ Nick-End Labeling; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012171:Retinal Vessels / Q000166:cytology* / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D034421:Sus scrofa; D013778:Tetrazolium Salts; D013844:Thiazoles; D019700:Thrombospondin 1 / Q000378:metabolism*
chemical_list: D001095:Arachidonic Acids; D017931:DNA Primers; D013778:Tetrazolium Salts; D013844:Thiazoles; D019700:Thrombospondin 1; D009569:Nitric Oxide; C022616:thiazolyl blue