Aldose reductase-regulated tumor necrosis factor-α production is essential for high glucose-induced vascular smooth muscle cell growth
Aldose reductase-regulated tumor necrosis factor-α production is essential for high glucose-induced vascular smooth muscle cell growth
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DOI：
10.1210/en.2007-0512
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发表时间：
2007-09-01
期刊：
影响因子：
4.8
通讯作者：
Srivastava, Satish K.
中科院分区：
文献类型：
--
作者：
Ramana, Kota V.;Tammali, Ravinder;Srivastava, Satish K.
糖尿病与细胞因子生成增加和组织炎症有关，但细胞因子合成增加如何与糖尿病并发症的发生有因果关系尚不清楚。在这里，我们报告暴露于高(25 MM)葡萄糖，而不是等渗浓度的甘露醇或3-甲基葡萄糖，增加培养的大鼠和人的主动脉平滑肌细胞分泌肿瘤坏死因子-α。放线菌素D和放线菌亚胺可抑制肿瘤坏死因子-α的增加，提示肿瘤坏死因子-α基因的转录激活。蛋白激酶C(PKC)-Delta抑制剂(Rottlerin；EMD Biosciences，加利福尼亚州圣地亚哥)可以特异性地抑制高糖(HG)诱导的TNF-α的释放，但不能抑制PKC-β2抑制剂(CGP53353；Tcris Cookson Inc.，Ellisville，MO)，这表明PKC-Delta可能参与了HG信号转导。抑制AR也可阻止肿瘤坏死因子-αmRNA的增加。在培养液中加入抗肿瘤坏死因子-α抗体或可溶性肿瘤坏死因子受体1和2或RNA干扰消融肿瘤坏死因子-α可减弱核因子-kappaB的激活并阻止HG刺激的细胞生长。这些数据表明，AR是HG诱导的肿瘤坏死因子-α合成和释放所必需的。在体内，HG释放的肿瘤坏死因子-α导致自分泌刺激肿瘤坏死因子-α的合成，可能是糖尿病心血管并发症发生的关键步骤。阻断肿瘤坏死因子-α的自分泌效应可能是治疗糖尿病血管病变的有效策略。
Diabetes is associated with increased generation of cytokines and tissue inflammation, but it is unclear how increased cytokine synthesis is causally related to the development of diabetic complications. Here, we report that exposure to high (25 mM) glucose, but not iso-osmotic concentrations of mannitol or 3-methyl glucose, increased TNF-alpha secretion by rat and human aortic smooth muscle cells in culture. The increase in TNF-alpha production was prevented by actinomycin D and cycloheximide, indicating transcriptional activation of TNF-alpha gene. High glucose (HG)-induced TNF-alpha release was specifically inhibited by protein kinase C ( PKC)-delta inhibitor ( Rottlerin; EMD Biosciences, San Diego, CA), but not PKC-beta 2 inhibitor (CGP53353; Tocris Cookson Inc., Ellisville, MO), indicating the possible involvement of PKC-delta in HG signaling.TNF-alpha secretion was also prevented by pretreating cells with aldose reductase (AR) inhibitors, sorbinil or tolrestat and in cells treated with antisense AR mRNA. Inhibition of AR also prevented the increase in TNF-alpha mRNA. Addition of anti-TNF-alpha antibodies or soluble TNF-alpha receptors 1 and 2 to the medium or RNA interference ablation of TNF-alpha attenuated nuclear factor-kappa B activation and prevented HG-stimulated cell growth. These data indicate that AR is required for HG-induced TNF-alpha synthesis and release. In vivo, the release of TNF-alpha by HG leading to autocrine stimulation of TNF-alpha synthesis may be a critical step in the development of the cardiovascular complications of diabetes. Interruption of the autocrine effects of TNF-alpha may be a useful strategy for treating diabetic vasculopathies.