Trans-arachidonic acids generated during nitrative stress induce a thrombospondin-1-dependent microvascular degeneration

Elsa Kermorvant-Duchemin, Florian Sennlaub, Mirna Sirinyan, Sonia Brault, Gregor Andelfinger, Amna Kooli, Stéphane Germain, Huy Ong, Pedro D'Orleans-Juste, Fernand Gobeil, Tang Zhu, Chantal Boisvert, Pierre Hardy, Kavita Jain, J R Falck, Michael Balazy, Sylvain Chemtob

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84 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1339-1345
Number of pages7
JournalNature medicine
Volume11
Issue number12
DOIs
StatePublished - Dec 2005

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Kermorvant-Duchemin, E., Sennlaub, F., Sirinyan, M., Brault, S., Andelfinger, G., Kooli, A., Germain, S., Ong, H., D'Orleans-Juste, P., Gobeil, F., Zhu, T., Boisvert, C., Hardy, P., Jain, K., Falck, J. R., Balazy, M., & Chemtob, S. (2005). Trans-arachidonic acids generated during nitrative stress induce a thrombospondin-1-dependent microvascular degeneration. Nature medicine, 11(12), 1339-1345. https://doi.org/10.1038/nm1336