O-GlcNAc modification of NFκB p65 inhibits TNF-α-induced inflammatory mediator expression in rat aortic smooth muscle cells.
O-GlcNAc modification of NFκB p65 inhibits TNF-α-induced inflammatory mediator expression in rat aortic smooth muscle cells.
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DOI：
10.1371/journal.pone.0024021
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Oparil S
中科院分区：
文献类型：
--
作者：
Xing D;Gong K;Feng W;Nozell SE;Chen YF;Chatham JC;Oparil S
我们已经表明，葡萄糖胺（GlcN）或O-（2-乙酰氨基-2-脱氧-D-吡喃葡萄糖基亚基）氨基-N-苯基氨基甲酸酯（PUGNAc）处理增强O-连接-N-乙酰葡萄糖胺（O-GlcNAc）蛋白修饰，并减弱炎症介质表达，白细胞浸润和球囊损伤大鼠颈动脉中的新生内膜形成，并已确定动脉平滑肌细胞（SMC）作为损伤反应中的靶细胞。NFκB信号通路介导了炎症基因的表达和损伤动脉的新生内膜形成。NFκB的p65亚基的磷酸化是NFκB转录激活所必需的。本研究验证了GlcN或PUGNAc处理通过增强O-GlcNAc化和抑制TNF-α诱导的NFκB p65磷酸化，从而抑制NFκB信号传导，从而保护血管SMC免受肿瘤坏死因子（TNF）-α诱导的炎症应激的假设。用GlcN（5 mM）、PUGNAc（10−4 M）或溶剂预处理静息大鼠主动脉SMC，然后用TNF-α（10 ng/ml）刺激。两种处理均抑制TNF-α诱导的趋化因子[姜黄素诱导的中性粒细胞趋化因子（CINC）-2β和单核细胞趋化蛋白（MCP）-1]和粘附分子[血管细胞粘附分子（VCAM）-1和P-选择素]的表达。两种处理均抑制TNF-α诱导的NFκB p65活化和启动子活性，增加NFκB p65 O-GlcNAc酰化并抑制NFκB p65丝氨酸536处的磷酸化，从而促进IκBα与NFκB p65结合。O-GlcNAc修饰与NFκB p65的磷酸化之间存在相互关系，因此增加的NFκB p65 O-GlcNAc修饰通过抑制NFκB p65信号传导抑制TNF-α诱导的炎症介质表达。这些发现为我们先前的观察提供了机制基础，即GlcN和PUGNAc治疗抑制急性腔内动脉损伤诱导的炎症和重塑。
We have shown that glucosamine (GlcN) or O-(2-acetamido-2-deoxy-D-glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc) treatment augments O-linked-N-acetylglucosamine (O-GlcNAc) protein modification and attenuates inflammatory mediator expression, leukocyte infiltration and neointima formation in balloon injured rat carotid arteries and have identified the arterial smooth muscle cell (SMC) as the target cell in the injury response. NFκB signaling has been shown to mediate the expression of inflammatory genes and neointima formation in injured arteries. Phosphorylation of the p65 subunit of NFκB is required for the transcriptional activation of NFκB. This study tested the hypothesis that GlcN or PUGNAc treatment protects vascular SMCs against tumor necrosis factor (TNF)-α induced inflammatory stress by enhancing O-GlcNAcylation and inhibiting TNF-α induced phosphorylation of NFκB p65, thus inhibiting NFκB signaling. Quiescent rat aortic SMCs were pretreated with GlcN (5 mM), PUGNAc (10−4 M) or vehicle and then stimulated with TNF-α (10 ng/ml). Both treatments inhibited TNF-α-induced expression of chemokines [cytokine-induced neutrophil chemoattractant (CINC)-2β and monocyte chemotactic protein (MCP)-1] and adhesion molecules [vascular cell adhesion molecule (VCAM)-1 and P-Selectin]. Both treatments inhibited TNF-α induced NFκB p65 activation and promoter activity, increased NFκB p65 O-GlcNAcylation and inhibited NFκB p65 phosphorylation at Serine 536, thus promoting IκBα binding to NFκB p65. There is a reciprocal relationship between O-GlcNAcylation and phosphorylation of NFκB p65, such that increased NFκB p65 O-GlcNAc modification inhibits TNF-α-Induced expression of inflammatory mediators through inhibition of NFκB p65 signaling. These findings provide a mechanistic basis for our previous observations that GlcN and PUGNAc treatments inhibit inflammation and remodeling induced by acute endoluminal arterial injury.
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影响因子：
3.5
作者：
Gouze, JN;Bianchi, A;Bordji, K
通讯作者：
Bordji, K
DOI：
10.1006/bbrc.1995.2204
发表时间：
1995-08-24
影响因子：
3.1
作者：
AUTIERI, MV;YUE, TL;OHLSTEIN, E
通讯作者：
OHLSTEIN, E
影响因子：
4.8
作者：
Ohtsuka, T;Kubota, A;Tsurufuji, S
通讯作者：
Tsurufuji, S
影响因子：
2.9
作者：
Cheng, XG;Cole, RN;Hart, GW
通讯作者：
Hart, GW
影响因子：
11.4
作者：
Duran, A;Diaz-Meco, MT;Moscat, J
通讯作者：
Moscat, J