Transition metals redox: reviving an old plot for diabetic vascular disease

Considerable effort over the past 25 years has focused on the role of oxidant stress in aging and in the pathogenesis of age-related diseases — diabetes, Alzheimer’s disease, end-stage renal disease, and atherosclerosis, among others. Research on redox signaling and the chemistry of the aging process has led to major insights, including the identification of oxidant stress–responsive transcription factors, such as NF-κB, which regulate tissue remodeling and therefore control the progression of pathological lesions; the role of mitochondria in generating reactive oxygen species and activating apoptotic pathways; the role of sulfhydryl homeostasis in redox signaling; and the development of mass spectrometry methods to identify and quantify protein damage in aging or stressed tissues. Because of the prevalence and the dire consequences of the diseases involved, the stakes in this field are high. However, despite the great interest in developing drugs that might block oxidant or carbonyl stress, clinical studies involving antioxidant or carbonyl-trapping agents have had mixed success, suggesting a greater degree of complexity than anticipated. Thus, in the diabetic rat, treatment with various antioxidants or carbonyl-trapping agents has had impressive effects in delaying, if not altogether preventing, complications of diabetes such as cataracts, retinopathy, nephropathy, vascular abnormalities, nerve conduction velocity, plasma lipid oxidation, and fetal malformations. In the diabetic human, conversely, while intra-arterial infusion of vitamin C improved endothelium-dependent vasodilation (1) and oral intake of vitamin E improved retinal blood flow and creatinine clearance (2), chronic treatment with vitamin E did not reduce cardiovascular risk (3). Similarly, the antioxidant α-lipoic acid decreased plasma hydroperoxides in diabetic subjects but had equivocal efficacy in polyneuropathy and cardiac autonomic neuropathy (4, 5). A similar “antioxidant paradox” has also been observed in other diseases associated with oxidant stress (6).