Tyrosine nitration of prostacyclin synthase is associated with enhanced retinal cell apoptosis in diabetes.
The risk of diabetic retinopathy is associated with the presence of both oxidative stress and toxic eicosanoids. Whether oxidative stress actually causes diabetic retinopathy via the generation of toxic eicosanoids, however, remains unknown. The aim of the present study was to determine whether tyrosine nitration of prostacyclin synthase (PGIS) contributes to retinal cell death in vitro and in vivo. Exposure of human retinal pericytes to heavily oxidized and glycated LDL (HOG-LDL), but not native forms of LDL (N-LDL), for 24 hours significantly increased pericyte apoptosis, accompanied by increased tyrosine nitration of PGIS and decreased PGIS activity. Inhibition of the thromboxane receptor or cyclooxygenase-2 dramatically attenuated HOG-LDL-induced apoptosis without restoring PGIS activity. Administration of superoxide dismutase (to scavenge superoxide anions) or L-N(G)-nitroarginine methyl ester (L-NAME, a nonselective nitric oxide synthase inhibitor) restored PGIS activity and attenuated pericyte apoptosis. In Akita mouse retinas, diabetes increased intraretinal levels of oxidized LDL and glycated LDL, induced PGIS nitration, enhanced apoptotic cell death, and impaired blood-retinal barrier function. Chronic administration of tempol, a superoxide scavenger, reduced intraretinal oxidized LDL and glycated LDL levels, PGIS nitration, and retina cell apoptosis, thereby preserving the integrity of blood-retinal barriers. In conclusion, oxidized LDL-mediated PGIS nitration and associated thromboxane receptor stimulation might be important in the initiation and progression of diabetic retinopathy.
Section of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
Ming-Hui
MH
Zou
Hongliang
H
Li
Chaoyong
C
He
Mingkai
M
Lin
Timothy J
TJ
Lyons
Zhonglin
Z
Xie
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001813:Blood-Retinal Barrier; D002478:Cells, Cultured; D003497:Cyclic N-Oxides / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003930:Diabetic Retinopathy / Q000473:pathology*; D017127:Glycation End Products, Advanced; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D020286:Pericytes / Q000473:pathology; D017482:Receptors, Thromboxane / Q000378:metabolism; D012160:Retina / Q000378:metabolism / Q000473:pathology; D013113:Spin Labels; D013482:Superoxide Dismutase / Q000494:pharmacology; D019108:Tight Junctions / Q000187:drug effects; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology*; D000093844:Glycated Proteins
D000975:Antioxidants; D003497:Cyclic N-Oxides; D051546:Cyclooxygenase 2; D003577:Cytochrome P-450 Enzyme System; D017127:Glycation End Products, Advanced; D019746:Intramolecular Oxidoreductases; D008077:Lipoproteins, LDL; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D017482:Receptors, Thromboxane; D013113:Spin Labels; D013482:Superoxide Dismutase; D014443:Tyrosine; C031797:glycated lipoproteins, LDL; D000093844:Glycated Proteins; C099252:oxidized low density lipoprotein; C002744:3-nitrotyrosine; C022461:prostacyclin synthetase; C001803:tempol