Oxidative Stress, VEGF and Retinopathy

生长因子如血管内皮生长因子（VEGF）已被认为在长期糖尿病并发症的发展中发挥作用，包括增殖性和非增殖性糖尿病视网膜病变。VEGF在许多类型的视网膜细胞中表达，包括Muller细胞和视网膜色素上皮细胞（RPE）。5例糖尿病视网膜病变患者玻璃体样本中VEGF水平升高。本课题将重点研究VEGF在糖尿病视网膜病变中表达增强的机制，重点关注RPE细胞。具体来说，本研究的目的是验证一种假设，即在糖尿病及其晚期糖基化终产物（AGE）中升高的活性内源性醛通过改变细胞内氧化还原状态上调RPE细胞中VEGF的表达。我们将重点研究酮醛甲基乙二醛（MeG）和α - β不饱和醛4-羟基壬烯醛（4HNE）来验证这一假设。我们将其命名为糖尿病并发症的醛（氧化）应激模型。具体目的是：1)证明MeG、4HNE及其AGE可改变细胞内氧化还原状态，导致RPE细胞中VEGF表达上调。2)阐明MeG、4HNE及其AGE改变VEGF表达的机制。3)评价抗氧化策略对MeG、4HNE及其AGE的影响。醛（氧化）应激模型强调除葡萄糖外羰基化合物在糖尿病视网膜病变病因学中的作用。为高血糖->氧化应激->生长因子->糖尿病视网膜病变提供了一个可验证的模型。

Growth factors such as vascular endothelial growth factor (VEGF) have been suggested to play a role in the development of long-term diabetic complications including both proliferative and non-proliferative diabetic retinopathy. VEGF is expressed by a number of cell types in the retina including Muller cells and retinal pigmented epithelial (RPE) cells. VEGF levels are elevated in vitreous body samples from five subjects with diabetic retinopathy. This proposal will focus on the mechanism of enhanced VEGF expression in diabetic retinopathy, with emphasis on RPE cells. Specifically, the objective of this study is to test the hypothesis that reactive endogenous aldehydes that are elevated in diabetes and their advanced Glycation Endproducts (AGE) up-regulate expression of VEGF in RPE cells through alterations of intracellular redox status. The proposed studies will focus on the ketoaldehyde methylglyoxal (MeG) and the alpha-beta unsaturated aldehyde 4- hydroxynonenal (4HNE) to test the hypothesis. We designate this the Aldehyde (Oxidative) Stress Model of Diabetic Complications. The Specific Aims are: 1) To demonstrate that MeG, 4HNE and their AGE can alter intracellular redox status, resulting in up-regulation of VEGF expression in RPE cells. 2) To elucidate the mechanisms by which MeG, 4HNE and their AGE alter expression of VEGF. 3) To evaluate anti-oxidant strategies for countering the effects of MeG, 4HNE and their AGE. The Aldehyde (Oxidative) Stress Model emphasizes the role of carbonyl compounds in addition to glucose in the etiology of diabetic retinopathy. It provides a testable model that connects hyperglycemia-> oxidative stress-> growth factors-> diabetic retinopathy.