Inhibition of aldose reductase attenuates TNF-alpha-induced expression of adhesion molecules in endothelial cells.
Increased expression of adhesion molecules by the activated endothelium is a critical feature of vascular inflammation associated with several disease states such as atherosclerosis. However, mechanisms regulating the endothelial induction of adhesion molecules are not entirely clear. Herein we report that inhibition of the polyol pathway enzyme aldose reductase (AR) prevents the increase in ICAM-1 and VCAM-1 in human umbilical vein endothelial cells (HUVECs) and decreases monocyte adhesion to these cells. In TNF-alpha-stimulated HUVECs, treatment with AR inhibitors sorbinil and tolrestat diminished NF-kappaB activity, phosphorylation and degradation of Ikappa-Balpha, and the nuclear translocation of NF-kappaB. Inhibition of AR abrogated TNF-alpha-induced activation and membrane translocation of PKC, and antisense ablation of AR prevented both TNF-alpha-induced PKC and NF-kappaB activation. However, inhibition of AR did not prevent phorbol ester-induced activation of PKC or NF-kappaB, indicating that inhibition of AR does prevents events upstream of PKC activation. These results identify a novel regulator of endothelial activation and suggest that AR is an obligatory mediator of TNF-alpha signaling leading to an increase in the expression of adhesion molecules and increased binding of monocytes to the endothelium.
Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, Texas 77555, USA.
Kota V
KV
Ramana
Aruni
A
Bhatnagar
Satish K
SK
Srivastava
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D048289:Imidazolidines / Q000494:pharmacology; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis* / Q000235:genetics; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D014471:Umbilical Veins; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis* / Q000235:genetics
D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D048289:Imidazolidines; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009281:Naphthalenes; D020319:Oligodeoxyribonucleotides, Antisense; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C040550:tolrestat; D018799:Intercellular Adhesion Molecule-1; D000072000:NF-KappaB Inhibitor alpha; D000449:Aldehyde Reductase; D011493:Protein Kinase C; C026411:sorbinil