Abstract
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-α-stimulated HUVECs, treatment with AR inhibitors sorbinil and tolrestat diminished NF-κB activity, phosphorylation and degradation of Iκ-Bα, and the nuclear translocation of NF-κB. Inhibition of AR abrogated TNF-α-induced activation and membrane translocation of PKC, and antisense ablation of AR prevented 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1209-1218 |
| Number of pages | 10 |
| Journal | FASEB Journal |
| Volume | 18 |
| Issue number | 11 |
| DOIs | |
| State | Published - Aug 2004 |
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Keywords
- Monocyte and adhesion molecules
- NF-κB
- PKC activity
ASJC Scopus subject areas
- Agricultural and Biological Sciences (miscellaneous)
- Biochemistry, Genetics and Molecular Biology(all)
- Biochemistry
- Cell Biology
Cite this
Inhibition of aldose reductase attenuates TNF-α-induced expression of adhesion molecules in endothelial cells. / Ramana, Kota; Bhatnagar, Aruni; Srivastava, Satish.
In: FASEB Journal, Vol. 18, No. 11, 08.2004, p. 1209-1218.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Inhibition of aldose reductase attenuates TNF-α-induced expression of adhesion molecules in endothelial cells
AU - Ramana, Kota
AU - Bhatnagar, Aruni
AU - Srivastava, Satish
PY - 2004/8
Y1 - 2004/8
N2 - 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-α-stimulated HUVECs, treatment with AR inhibitors sorbinil and tolrestat diminished NF-κB activity, phosphorylation and degradation of Iκ-Bα, and the nuclear translocation of NF-κB. Inhibition of AR abrogated TNF-α-induced activation and membrane translocation of PKC, and antisense ablation of AR prevented 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.
AB - 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-α-stimulated HUVECs, treatment with AR inhibitors sorbinil and tolrestat diminished NF-κB activity, phosphorylation and degradation of Iκ-Bα, and the nuclear translocation of NF-κB. Inhibition of AR abrogated TNF-α-induced activation and membrane translocation of PKC, and antisense ablation of AR prevented 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.
KW - Monocyte and adhesion molecules
KW - NF-κB
KW - PKC activity
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U2 - 10.1096/fj.04-1650com
DO - 10.1096/fj.04-1650com
M3 - Article
VL - 18
SP - 1209
EP - 1218
JO - FASEB Journal
JF - FASEB Journal
SN - 0892-6638
IS - 11
ER -