Aldose reductase mediates mitogenic signaling in vascular smooth muscle cells.
Abnormal vascular smooth muscle cell (VSMC) proliferation is a key feature of atherosclerosis and restenosis; however, the mechanisms regulating growth remain unclear. Herein we show that inhibition of the aldehyde-metabolizing enzyme aldose reductase (AR) inhibits NF-kappa B activation during restenosis of balloon-injured rat carotid arteries as well as VSMC proliferation due to tumor necrosis factor alpha (TNF-alpha) stimulation. Inhibition of VSMC growth by AR inhibitors was not accompanied by increase in cell death or apoptosis. Inhibition of AR led to a decrease in the activity of the transcription factor NF-kappa B in culture and in the neointima of rat carotid arteries after balloon injury. Inhibition of AR in VSMC also prevented the activation of NF-kappa B by basic fibroblast growth factor (bFGF), angiotensin-II (Ang-II), and platelet-derived growth factor (PDGF-AB). The VSMC treated with AR inhibitors showed decreased nuclear translocation of NF-kappa B and diminished phosphorylation and proteolytic degradation of I kappa B-alpha. Under identical conditions, treatment with AR inhibitors also prevented the activation of protein kinase C (PKC) by TNF-alpha, bFGF, Ang-II, and PDGF-AB but not phorbol esters, indicating that AR inhibitors prevent PKC stimulation or the availability of its activator but not PKC itself. Treatment with antisense AR, which decreased the AR activity by >80%, attenuated PKC activation in TNF-alpha, bFGF, Ang-II, and PDGF-AB-stimulated VSMC and prevented TNF-alpha-induced proliferation. Collectively, these data suggest that inhibition of NF-kappa B may be a significant cause of the antimitogenic effects of AR inhibition and that this may be related to disruption of PKC-associated signaling in the AR-inhibited cells.
Ramana
Kota V
KV
Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, Texas 77555, USA.
Chandra
Deepak
D
Srivastava
Sanjay
S
Bhatnagar
Aruni
A
Aggarwal
Bharat B
BB
Srivastava
Satish K
SK
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D002339:Carotid Arteries / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D048289:Imidazolidines; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007093:Imidazoles; D048289:Imidazolidines; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D000449:Aldehyde Reductase; C026411:sorbinil