Abstract
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.
Highlights
Aldose reductase (AR)1 catalyzes the reduction of a wide range of aldehydes [1]
Recent studies showing that AR is an excellent catalyst for the reduction of lipid peroxidation-derived aldehydes and their glutathione conjugates [3,4,5,6,7,8] suggest that in contrast to its injurious role during diabetes, under normal glucose concentration, AR may be involved in protection against oxidative and electrophilic stress
Inhibition of AR Diminishes NF-B Activation—We have previously reported that inhibition of AR prevents serum-induced vascular smooth muscle cells (VSMC) growth in culture and decreases neointima formation in balloon-injured carotid arteries [10]
Summary
Treatment with antisense AR, which decreased the AR activity by >80%, attenuated PKC activation in TNF-␣, bFGF, Ang-II, and PDGF-AB-stimulated VSMC and prevented TNF-␣-induced proliferation These data suggest that inhibition of NF-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. The expression of the enzyme is increased under several pathological conditions associated with increased oxidative or electrophilic stress such as iron overload [14], alcoholic liver disease [15], heart failure [16], myocardial ischemia [17], vascular inflammation [11], and restenosis [10] Together, these observations provide strong support to the view that AR protects against the toxicity of electrophilic aldehydes and their glutathione conjugates by reducing them to less toxic or metabolic inert alcohols. We examined the participation of AR in VSMC mitogenesis in response to TNF-␣, which is the main mitogen driving neointima formation in vivo [25, 26], and various growth factors
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