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Article
Nature Medicine 11, 1339 - 1345 (2005)
Published online: 27 November 2005 | doi:10.1038/nm1336
Trans-arachidonic acids generated during nitrative stress induce a thrombospondin-1–dependent microvascular degeneration
Elsa Kermorvant-Duchemin1,9, Florian Sennlaub1,2,9, Mirna Sirinyan1,3, Sonia Brault1,3, Gregor Andelfinger1, Amna Kooli1,3, Stéphane Germain4, Huy Ong5, Pedro d'Orleans-Juste6, Fernand Gobeil Jr6, Tang Zhu1, Chantal Boisvert1, Pierre Hardy1, Kavita Jain7, J Russel Falck8, Michael Balazy7 & Sylvain Chemtob1,3
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 NO2
-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.
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