期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 277, 期 35, 页码 32063-32070出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M202126200
关键词
-
资金
- NHLBI NIH HHS [HL59378, HL55477] Funding Source: Medline
- NIDDK NIH HHS [DK 36118] Funding Source: Medline
- NIEHS NIH HHS [R01 ES017260] Funding Source: Medline
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-kappaB 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-kappaB in culture and in the neointima of rat carotid arteries after balloon injury. Inhibition of AR in VSMC also prevented the activation of NF-kappaB 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-kappaB and diminished phosphorylation and proteolytic degradation of IkappaB-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-kappaB 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据