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Vascular complications of diabetes: Studies on NFAT

Vascular complications of diabetes: Studies on NFAT (Nuclear Factor of Activated T-cells) as a novel target for the treatment of atherosclersis and vascular dysfunction in diabetes.

Diabetes-induced macro- and microvascular complications are the major cause of morbidity and mortality in diabetic patients. Based on current trends, the rising incidence of diabetes (expected to reach 380 million people worldwide by 2025), will undoubtedly equate to increased cardiovascular mortality. Despite the vast clinical experience linking diabetes, obesity and the metabolic syndrome to vascular disease, little is understood regarding the mechansims connecting hyperglycemia to atherosclerosis.

Thus, one objective of this study is to determine he role of the transcription factor NFAT (Nuclear Factor of Activated T-cells), which we recently identified as a novel glucose-sensor in the vascular wall, in diabetes-driven atherosclerosis; and to explore the potential benefit of therapeutic inhibition of NFAT activity.

Diabetes is also associated with complications of the microcirculation giving rise to the clinical features of retinopathy, nephropathy and neuropathy. Central to the development of vascular disease is endothelial dysfunction, which appears well before any clinical sign, but importantly is potentially reversible. It is currently believed that hyperglycemia induces microvascular damage probably through a single common pathway - increased intracellular oxidative stress - linking four major mechanisms, namely the polyol pathway, advanced glycation end-products (AGEs) formation, the protein kinase C (PKC)-diacylglycerol (DAG) and the hexosamine pathways. We would like to challenge this idea and propose that NFAT activation is a key event for development of microvascular complications, representing an additional link between hyperglycemia and microvascular damage.

Thus, a second objective of this study is to investigate if NFAT activation leads to early development of endothelial dysfunction and to examine the effects of NFAT blockade on the microvasculature.

Macro- and microvascular complications of dibetes impose an immense burden on the quality of life of patients and account for more than 10% of health costs in Europe. Therefore, efforts to prevent and/or limit progression of these devastating complications are well motivated.