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S. X. Zhang, J. Li, J. Wang, J.-X. Ma; Angiostatin Protects Blood-Retina Barrier Through Anti-Inflammatory and Anti-Oxidative Activity in Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1329.
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© ARVO (1962-2015); The Authors (2016-present)
Angiostatin is a potent endogenous angiogenic inhibitor. Our previous study demonstrated that angiostain reduces retinal vascular leakage in diabetic animals. However, the mechanism is not well studied. We hypothesize that the salutary effect of angiostatin on permeability is through regulation of inflammation and oxidative stress. In present study, we investigated the regulation of angiostatin on pro/anti-inflammatory factors and anti-oxidative enzymes in retinal endothelial cells and in diabetic retina.
Diabetes was induced by STZ into adult BN rats. One week after being diabetic, the rats were randomly assigned to receive intravenous injection of adenovirus expressing human angiostatin (Ad-Ang)or green fluorescent protein (Ad-GFP), or no injection (n=5) for 3 weeks. Expression of tight junctional proteins and inflammatory factors in the retina were determined. In addition, bovine retinal capillary endothelial cells (RCEC) were exposed to normal glucose (5 mM), high glucose (25 mM) medium, hypoxia (2% oxygen) or lipopolysaccharide (LPS), with or without angiostatin (5-50 µM) for 24 h. Expression of pro/anti-inflammatory factors and anti-oxidative enzymes were determined by Western blot analysis.
Expression of tight junctional protein occludin was significantly decreased in the retina of diabetic rats and restored by Ad-Ang but not by Ad-GFP treatment. Moreover, retinal tumor necrosis factor (TNF-α) levels were decreased by Ad-Ang but not by Ad-GFP. In cultured RCEC, expression of intercellular cell adhesion molecule-1 (ICAM-1) was significantly increased by LPS in a dose-dependent manner and decreased by angiostain at 10 nM. Moreover, angiostatin increased expression of pigment epithelium derived factor (PEDF) and decreased VEGF in RCEC in normal and high glucose medium. Additional studies demonstrated that angiostatin significantly up-regulated superoxide dismutase 2 (SOD2) expression in RCECs under normal, high glucose and hypoxia conditions.
Taken together, the results form this study demonstrate that angiostatin is a potent regulator of inflammation in the retina. Up-regulation of anti-inflammatory factor, i.e. PEDF and down-regulation of pro-inflammatory factors, i.e. VEGF, TNF-α and ICAM-1 contribute to the effect of angiostatin on reducing vascular permeability Regulation of oxidative/anti-oxidative system in the retina by angiostatin warrant more future study to elucidate the mechanisms for its anti-inflammatory and anti-permeability effects in diabetic retinopathy.
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