Role of aldose reductase in TNF-alpha-induced apoptosis of vascular endothelial cells.
Apoptosis of vascular endothelial cells (VECs) and concomitant proliferation of the underlying vascular smooth muscle cells (VSMCs) in large arteries are the key features of atherosclerosis and restenosis. However, the mechanisms underlying endothelial cell death and abnormal smooth muscle cell proliferation during the development of vascular lesions remain unclear. We have previously demonstrated that treatment with inhibitors of the aldehyde-metabolizing enzyme and aldose reductase (AR) attenuates restenosis of balloon-injured rat carotid arteries. The inhibition of AR also prevents the apoptosis of VECs induced by the tumor necrosis factor-alpha (TNF-alpha). Apoptosis of the VECs was determined by the incorporation of [3H]-thymidine and the activation of caspase-3. Stimulation of the VECs with TNF-alpha led to an increase in the DNA-binding activity of the transcription factor, nuclear factor-kappa binding protein (NF-kappaB) and the induction of the adhesion molecule (ICAM)-1. Treatment of VECs with the AR inhibitor, tolrestat, prevented the activation of NF-kappaB and diminished ICAM-1 induction stimulated by TNF-alpha. These results indicate an obligatory requirement of AR activity in the transduction of intracellular signaling initiated by the ligation of the TNF-alpha receptors leading to the activation of NF-kappaB. Although the specific signaling events interrupted by AR inhibition remain unknown, our results suggest that product(s) of AR catalysis may be essential for NF-kappaB activation. These observations could form the basis of future investigations into the therapeutic utility of AR inhibitors in preserving endothelial function and integrity during atherosclerosis and diabetes.
Chandra
Deepak
D
Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, TX 77555, USA.
Ramana
Kota V
KV
Friedrich
Brian
B
Srivastava
Sanjay
S
Bhatnagar
Aruni
A
Srivastava
Satish K
SK
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D004730:Endothelium, Vascular / Q000166:cytology* / Q000201:enzymology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D015854:Up-Regulation
D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D000449:Aldehyde Reductase