Open AccessTrans-arachidonic acids generated during nitrative stress induce a thrombospondin-1–dependent microvascular degeneration
Author(s) -
Elsa KermorvantDuchemin,
Florian Sennlaub,
Mirna Sirinyan,
Sonia Brault,
Grégor Andelfinger,
Amna Kooli,
Stéphane Germain,
Huy Ong,
Pedro D’Orléans-Juste,
Fernand Gobeil,
Tang Zhu,
Chantal Boisvert,
Pierre Hardy,
Kavita Jain,
John R. Falck,
Michael Balazy,
Sylvain Chemtob
Publication year - 2005
Publication title -
nature medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 19.536
H-Index - 547
eISSN - 1546-170X
pISSN - 1078-8956
DOI - 10.1038/nm1336
Subject(s) - arachidonic acid , chemistry , thrombospondin , in vivo , macular degeneration , retinal , oxidative stress , microbiology and biotechnology , thrombospondin 1 , biochemistry , biology , angiogenesis , cancer research , medicine , enzyme , metalloproteinase , ophthalmology
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.