Aldose reductase regulates TNF-α-induced cell signaling and apoptosis in vascular endothelial cells

In this study, we examined the role of aldose reductase (AR) in regulating the cytotoxic effects of TNF-alpha on human umbilical vein endothelial cells. Inhibition of AR by sorbinil or tolrestat prevented TNF-alpha-induced increase in Bax and Bak and the downregulation of Bcl-2. Inhibition of AR abrogated AP-1 DNA binding activity and prevented the activation of caspase-3, JNK, and p38 MAPK in cells stimulated by TNF-alpha. Exposure to TNF-alpha also induced apoptotic cell death, which was attenuated by AR inhibition or antisense ablation. These observations suggest that AR is a critical regulator of TNF-alpha-induced apoptotic signaling in endothelial cells. (C) 2004 Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies.