Aldose reductase mediates mitogenic signaling in vascular smooth muscle cells
Aldose reductase mediates mitogenic signaling in vascular smooth muscle cells
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DOI：
10.1074/jbc.m202126200
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发表时间：
2002-08-30
影响因子：
4.8
通讯作者：
Srivastava, SK
中科院分区：
文献类型：
--
作者：
Ramana, KV;Chandra, D;Srivastava, SK
血管平滑肌细胞（VSMC）的异常增殖是动脉粥样硬化和再狭窄的一个重要特征，但其生长调节机制尚不清楚。在此，我们表明，抑制血管紧张素代谢酶醛糖还原酶（AR）抑制NF-κ B激活过程中的球囊损伤大鼠颈动脉再狭窄以及VSMC增殖由于肿瘤坏死因子α（TNF-α）的刺激。AR抑制剂抑制VSMC生长并不伴随细胞死亡或凋亡的增加。AR的抑制导致转录因子NF-κ B在培养物和球囊损伤后大鼠颈动脉新生内膜中的活性降低。抑制VSMC中的AR也阻止了碱性成纤维细胞生长因子（bFGF）、血管紧张素-II（Ang-II）和血小板衍生生长因子（PDGF-AB）对NF-κ B的激活。用AR抑制剂处理的VSMC显示NF-κ B的核转位减少，IkappaB-α的磷酸化和蛋白水解降解减少。在相同的条件下，用AR抑制剂治疗也阻止了TNF-α、bFGF、Ang-II和PDGF-AB对蛋白激酶C（PKC）的激活，但没有佛波醇酯，这表明AR抑制剂阻止了PKC刺激或其激活剂的可用性，但没有阻止PKC本身。用反义AR处理，使AR活性降低> 80%，减弱了TNF-α、bFGF、Ang-II和PDGF-AB刺激的VSMC中的PKC活化，并阻止了TNF-α诱导的增殖。总的来说，这些数据表明NF-κ B的抑制可能是AR抑制的抗有丝分裂作用的重要原因，并且这可能与AR抑制细胞中PKC相关信号传导的破坏有关。
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.