Carboxyethylpyrrole Adducts, Age-related Macular Degeneration and Neovascularization

摘要

Choroidal neovascularization (CNV) in late stage age-related macular degeneration (AMD) involves abnormal vessel growth from the choriocapillaris through Brach's membrane and the retinal pigment epithelium (RPE) and accounts for more than 80% of the severe debilitating vision loss in all AMD patients. The molecular mechanisms associated with AMD pathogenesis and the development of CNV remain poorly understood. We hypothesize that oxidative protein modifications are primary catalysts in AMD pathogenesis and play a role in the development of CNV (Crabb et al., 2002). Oxidative damage has long been suspected of contributing to AMD (Beatty et al., 2000), supported by indirect evidence that smoking increases the risk of AMD (Seddon et al., 1996) and that antioxidant vitamins and zinc can slow disease progression for select individuals (AREDS, 2001). Our proteomic study of drusen established a direct link between oxidative damage and AMD by demonstrating elevated carboxyethylpyrrole (CEP) adducts in AMD Bruch's membrane (Crabb et al., 2002). CEP protein adducts are uniquely generated from oxidation of docosahexaenoate (DHA)-containing lipids and DHA accounts for approximately 80 mol% of the polyunsaturated lipids in photoreceptor outer segments (Fliesler and Anderson, 1983). CEP adducts are also significantly elevated in plasma from AMD donors, as are CEP autoantibodies(Gu et al., 2003), both of which may have utility as biomarkers for monitoring AMD therapeutic efficacies. The high levels of CEP-adducts in AMD are likely associated with the high levels of DHA in photore-ceptors, the fact that DHA is the most oxidizable fatty acid in humans, and the high photooxidative stress in the retina (Fig. 1)