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Inhibition of aldose reductase attenuates TNF‐α‐induced expression of adhesion molecules in endothelial cells
Author(s) -
Ramana Kota V.,
Bhatnagar Aruni,
Srivastava Satish K.
Publication year - 2004
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-1650com
Subject(s) - cell adhesion molecule , microbiology and biotechnology , umbilical vein , chemistry , endothelium , aldose reductase , protein kinase c , endothelial activation , cell adhesion , vcam 1 , signal transduction , tumor necrosis factor alpha , sorbinil , phosphorylation , adhesion , biology , biochemistry , icam 1 , immunology , aldose reductase inhibitor , enzyme , in vitro , endocrinology , organic chemistry
Increased expression of adhesion mole‐ cules by the activated endothelium is a critical feature of vascular inflammation associated with several dis‐ ease states such as atherosclerosis. However, mecha‐ nisms regulating the endothelial induction of adhesion molecules are not entirely clear. Herein we report that inhibition of the polyol pathway enzyme aldose reduc‐ tase (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‐α‐stimulated HUVECs, treatment with AR inhibi‐ tors sorbinil and tolrestat diminished NF‐κB activity, phosphorylation and degradation of Iκ‐Bα, and the nuclear translocation of NF‐κB. Inhibition of AR abro‐ gated TNF‐α‐induced activation and membrane trans‐ location of PKC, and antisense ablation of AR pre‐ vented both TNF‐α‐induced PKC and NF‐κB activation. However, inhibition of AR did not prevent phorbol ester‐induced activation of PKC or NF‐κB, 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‐α signaling leading to an increase in the expression of adhesion molecules and increased binding of monocytes to the endothelium.— Ramana, K. V., Bhatnagar, A., Srivastava, S. K. Inhibi‐ tion of aldose reductase attenuates TNF‐α‐induced expression of adhesion molecules in endothelial cells. FASEB J. 18, 1209 –1218 (2004)