[Frontiers in Bioscience S3, 709-729, January 1, 2011]

Targeted antioxidant therapies in hyperglycemia-mediated endothelial dysfunction

Judy B. de Haan1, Mark E. Cooper2

1Oxidative Stress Laboratory, BakerIDI Heart and Diabetes Institute, Melbourne, Australia, 2Diabetic Complications Division, BakerIDI Heart and Diabetes Institute, Melbourne, Australia

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Oxidative stress and diabetes-mediated endothelial dysfunction
3.1. The vascular endothelium and vascular tone
3.2. The role of reactive oxygen species and NADPH Oxidase in diabetic vascular tissue
3.2.1. Consequences of increased superoxide: reductions in NO bioavailability 3.2.2 ..Consequences of increased peroxynitrite: implications for vascular function and inflammation
3.3. A role for antioxidant defence
3.3.1. Superoxide dismutase
3.3.2. Catalase
3.3.3. Glutathione peroxidase
3.3.3.1. The GPx1 knockout mouse: a model of increased oxidative stress
3.3.3.2. GPx1-/- mice are more susceptible to endothelial dysfunction
3.3.3.3. Diabetic ApoE/GPx1 double knockout Mice as a Model of accelerated Diabetes-Associated-Atherosclerosis
3.3.3.4. Diabetic ApoE/GPx1 dKO Mice as an Oxidative Stress Model of Diabetic Nephropathy
4. Novel antioxidants to limit diabetic micro- and macrovascular disease
4.1. Nox-inhibitors
4.2. SOD mimetics
4.3. The GPx1-mimetic Ebselen
4.3.1. Ebselen in an Experimental Model of Diabetes-Associated Atherosclerosis
4.3.2. Mechanistic Understanding of the Anti-Atherogenic action of Ebselen
4.4. Mitochondrially-targeted antioxidants
4.5. Bolstering antioxidant defences: The transcription factor Nrf2
4.6. Genetic manipulations to increase antioxidant defences.
5. Conclusion
6. Acknowledgements
7. References

1. ABSTRACT

Although intensive glycaemic and blood pressure control have reduced the risks of micro- and macrovascular complications, diabetes remains a major cause of cardiovascular events, end-stage renal failure, blindness and neuropathy. It is therefore imperative to understand the underlying mechanisms and to establish effective treatments to prevent, retard or reverse diabetic complications. One area of increased focus is the diabetic vascular endothelium. Hyperglycaemia triggers a cascade of events, not least an increase in reactive oxygen species (ROS) leading to enhanced oxidative stress, with its negative impact on endothelial function. In this review, we explore a unifying hypothesis that increased glucose-mediated ROS leads to endothelial dysfunction as the underpinning causative event triggering accelerated micro- and macrovascular complications. In particular, the consequences of deficiencies in the antioxidant enzyme, glutathione peroxidase, on endothelial dysfunction as a trigger of diabetic micro- and macrovascular complications, will be reviewed. Furthermore, novel antioxidant therapies will be highlighted. Specifically, use of Gpx1-mimetics holds promise as a targeted antioxidant approach and an alternative adjunct therapy to reduce diabetic complications.