Molecular pathology of oxidative stress in diabetic angiopathy: Role of mitochondrial and cellular pathways

Diabetes mellitus is characterized by chronic hyperglycaemia and a significant risk of developing micro- and macrovascular complications. Growing evidence suggests that increased oxidative stress, induced by several hyperglycaemia-activated pathways, is a key factor in the pathogenesis of endothelial dysfunction and vascular disease.Reactive oxidant molecules, which are produced at a high rate in the diabetic milieu, can cause oxidative damage of many cellular components and activate several pathways linked with inflammation and apoptosis. Among the mechanisms involved in oxidative stress generation, mitochondria and uncoupling proteins are of particular interest and there is growing evidence suggesting their pivotal role in the pathogenesis of diabetic complications. Other important cellular sources of oxidants include nicotinamide adenine dinucleotide phosphate oxidases and uncoupling endothelial nitric oxide synthase. In addition, diabetes is associated with reduced antioxidant defences, which generally contrast the deleterious effect of oxidant species. This concept underlines a potential beneficial role of antioxidant therapy for the prevention and treatment of diabetic vascular disease. However, large scale trials with classical antioxidants have failed to show a significant effect on major cardiovascular events, thus underlying the need of further investigations in order to develop therapies to prevent and/or delay the development of micro- and macrovascular complications.