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B. Zhang, J. Ma; Therapeutic Potential of SERPINA4, an Extracellular SERPIN Member, in the Ischemia-Induced Retinopathy. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2640.
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SERPINA4 belongs to the serine proteinase inhibitor (SERPIN) family, clade A. We have shown previously that SERPINA4 levels are decreased in the retina of a diabetic animal model and in the vitreous from diabetic patients, which may contribute to diabetic retinopathy (DR). It has been suggested that ischemia/hypoxia-induced oxidation, inflammation, fibrosis, and neovascularization are common pathological changes in DR. SERPINA4 has been shown to be a potent angiogenic inhibitor. The purpose of this study is to investigate whether SERPINA4 inhibits retinal oxidation, inflammation and fibrosis induced by diabetes and ischemia.
Retinal Müller cells, retinal pigment epithelial (RPE) cells and Retinal Capillary Endothelial Cells (RCEC) were treated by CoCl2 or 2% O2 to induce hypoxia. For the oxygen-induced retinopathy (OIR) model, newborn BN rats were exposed to 75% O2 from age of P7 to P12. Intravitreal injections of the protein or adenovirus were used to deliver SERPINA4. The fluorescence of the probe CM-H2DCFDA was measured to determine the intracellular ROS level. Inflammatory and fibrogenic factors were measured using western-blotting or ELASA.
In the OIR model, retinal vascular hyper-permeability was significantly reduced by SERPINA4 delivery. SERPINA4 increased the expression of occludin, a tight junction protein in the OIR retina and in the hypoxic retinal cell culture to the normal levels. At the same time, SERPINA4 blocked the over-expression of the pro-inflammatory factors and the fibrogenic factors, such as VEGF, TNF-α, ICAM-1, and CTGF, and inhibited the activation of the MAP kinase under hypoxia. Moreover, SERPINA4 significantly decreased reactive oxygen species (ROS) generation and up-regulated the expression of an endogenous anti-oxidant enzyme, the manganese superoxide dismutase (Mn-SOD / SOD2). DPI, an ROS inhibitor, and SOD2 both alleviated oxidation in retinal Müller cells exposed to hypoxia, and blocked the over-expression of VEGF and CTGF. On the other hand, the oxidant (H2O2) increased expression levels of VEGF and CTGF, same as the hypoxia treatment. These results suggest that oxidation was the upstream event in DR and the anti-oxidation activity of SERPINA4 is the potential mechanism responsible for its anti-inflammation and anti-fibrosis functions.
SERPINA4 is an anti-inflammatory and anti-fibrogenic factor. These effects may be mediated by its anti-oxidant activity. SERPINA4 has therapeutic potential for the DR.
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