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Activation of NF-E2-related factor-2 reverses biochemical dysfunction of endothelial cells induced by hyperglycemia linked to vascular disease

¹Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, University Hospital, Coventry CV2 2DX, U.K. and
²Department of Biological Sciences, University of Essex, Central Campus, Wivenhoe Park, Colchester, Essex CO4 3SQ, U.K.

OBJECTIVE–: Sulforaphane (SFN) is an activator of transcription factor NF-E2-related factor-2 (nrf2) that regulates gene expression through the promoter antioxidant response element (ARE). Nrf2 regulates the transcription of a battery of protective and metabolic enzymes. The aim of this study was to assess if activation of nrf2 by SFN in human microvascular endothelial cells prevents metabolic dysfunction in hyperglycemia.

RESEARCH DESIGN AND METHODS–: Human microvascular HMEC-1 endothelial cells were incubated in low and high glucose concentrations (5 and 30 mM) and activation of nrf2 assessed by nuclear translocation. The effect of SFN on multiple pathways of biochemical dysfunction, increased reactive oxygen species (ROS) formation, hexosamine pathway, protein kinase C pathway and increased formation of methylglyoxal, was assessed.

RESULTS–: Activation of nrf2 by SFN induced nuclear translocation of nrf2 and increased ARE-linked gene expression. For example, 3 - 5 fold increased expression of transketolase and glutathione reductase. Hyperglycemia increased the formation of ROS – an effect linked to mitochondrial dysfunction and prevented by SFN. ROS formation was increased further by knockdown of nrf2 and transketolase expression. This also abolished the counteracting effect of SFN, suggesting mediation by nrf2 and related increase of transketolase expression. SFN also prevented hyperglycemia-induced activation of the hexosamine and protein kinase C pathways, and prevented increased cellular accumulation and excretion of the glycating agent, methylglyoxal.

CONCLUSION–: We conclude that activation of nrf2 may prevent biochemical dysfunction and related functional responses of endothelial cells induced by hyperglycemia in which increased expression of transketolase has a pivotal role.

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