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Ruth Caldwell, S.Priya Narayanan, Modesto Rojas, Tahira Lemtalsi, Zhimin Xu, Kanjana Jittiporn, Erica Schenhals, Robert Caldwell, David Fulton, ; Overactive Arginase Causes Mitochondrial Dysfunction and Premature Endothelial Cell Senescence during Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4597.
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Our previous studies have shown that diabetes-induced vascular inflammation and impairment of endothelial-dependent vasorelaxation involve activation of the urea/ornithine producing enzyme arginase. Overactive arginase uncouples endothelial nitric oxide synthase (NOS), leading to increases in oxidative stress and decreases in NO bioavailability. These alterations have been linked to vascular injury and defective vascular repair during peripheral vascular disease by a mechanism involving stress-induced premature senescence of vascular endothelial cells (EC). Accelerated aging and premature senescence have been reported in diabetic patients at risk for developing peripheral vascular complications. However, EC senescence has not been addressed in diabetic retinopathy. Here we examined the potential role of overactive arginase in causing premature EC senescence and death during diabetic retinopathy.
Studies were performed in diabetic mice and high glucose-treated retinal vascular ECs treated with or without a specific arginase inhibitor. Mitochondrial dysfunction was determined by Mitosox Red imaging. Premature EC senescence was evaluated by assessing activity of the senescence marker SA β-galactosidase and Western blotting for the cell cycle negative regulator p16INK4a and putative upstream mediators of premature senescence [phosphorylation/activation of apoptosis signaling kinase 1 (p-ASK1), p-p38 MAPK and p-JNK]. Cell death was determined by TUNEL assay.
Our studies showed that increased arginase expression and activity in diabetic retinas, hyperglycemia-treated retinal ECs or retinal ECs transduced with arginase I are associated with decreased NO formation, mitochondrial dysfunction, premature EC senescence and increased EC death. Blockade of arginase limited these effects.
This study shows for the first time that diabetes/high glucose induced injury and impaired survival of vascular ECs is mediated by a mechanism of premature EC senescence. Furthermore our results suggest that excessive arginase activity contributes to EC dysfunction and injury by reducing NO, increasing oxidative stress and causing mitochondrial dysfunction, resulting in premature EC senescence.
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