Acute O-GlcNAcylation prevents inflammation-induced vascular dysfunction
Acute O-GlcNAcylation prevents inflammation-induced vascular dysfunction
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DOI：
10.1152/ajpheart.01175.2011
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发表时间：
2012-09-01
影响因子：
4.8
通讯作者：
Oparil, Suzanne
中科院分区：
文献类型：
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作者：
Hilgers, Rob H. P.;Xing, Dongqi;Oparil, Suzanne
Hilgers RH、Xing D、Gong K、Chen YF、Chatham JC、Oparil S。急性 O-GlcNAc 酰化可预防炎症引起的血管功能障碍。 Am J Physiol Heart Circ Physiol 303：H513-H522，2012。首次发表于 2012 年 7 月 9 日； doi:10.1152/ajpheart.01175.2011.-细胞蛋白O-连接的N-乙酰氨基葡萄糖(O-GlcNAc) 修饰(O-GlcNAcylation) 的急剧增加已被证明对心脏和脉管系统具有保护作用。我们假设 D-葡萄糖胺 (D-GlcN) 和 Thiamet-G 这两种通过不同机制增加蛋白质 O-GlcNAc 酰化的药物，通过抑制诱导型一氧化氮 (NO) 合酶 (iNOS) 表达来抑制 TNF-α 诱导的氧化应激和血管功能障碍。将大鼠主动脉环与 D-GlcN 或其渗透控制 L-葡萄糖 (L-Glc) 或与 Thiamet-G 或其载体对照 (H2O) 在 37 ℃ 孵育 3 小时，然后添加 TNF-α 或载体 (H2O) 21 小时。孵育后，将环安装在肌动描记器中以评估动脉反应性。主动脉环与 TNF-α 孵育 24 小时，导致 1) 对 60 mM K+ 溶液和去氧肾上腺素的收缩性降低，2) 对 ACh 和 P 物质的内皮依赖性松弛反应减弱，3) 与在不存在 TNF-α 的情况下培养的主动脉环相比，对 Ca2+ 离子载体 A-23187 和 NO 供体硝普钠的松弛反应未改变TNF-α。 D-GlcN 和 Thiamet-G 预处理可抑制 TNF-α 诱导的收缩力低下和内皮功能障碍。与对照组相比，用 D-GlcN 或 Thiamet-G 处理的主动脉段中的总蛋白 O-GlcNAc 水平显着升高。在 TNF-α 处理的环中，iNOS 蛋白的表达增加，并且通过用 D-GlcN 或 Thiamet-G 预处理可以减弱这种表达。在主动脉壁的内皮和中膜中检测到硝基酪酰化蛋白的密集免疫染色，表明 iNOS 产生的过氧亚硝酸盐增强。这些发现表明，蛋白质 O-GlcNAc 酰化的急剧增加至少部分通过抑制 iNOS 表达来预防 TNF-α 诱导的血管功能障碍。
Hilgers RH, Xing D, Gong K, Chen YF, Chatham JC, Oparil S. Acute O-GlcNAcylation prevents inflammation-induced vascular dysfunction. Am J Physiol Heart Circ Physiol 303: H513-H522, 2012. First published July 9, 2012; doi:10.1152/ajpheart.01175.2011.-Acute increases in cellular protein O-linked N-acetyl-glucosamine (O-GlcNAc) modification (O-GlcNAcylation) have been shown to have protective effects in the heart and vasculature. We hypothesized that D-glucosamine (D-GlcN) and Thiamet-G, two agents that increase protein O-GlcNAcylation via different mechanisms, inhibit TNF-alpha-induced oxidative stress and vascular dysfunction by suppressing inducible nitric oxide (NO) synthase (iNOS) expression. Rat aortic rings were incubated for 3h at 37 degrees C with D-GlcN or its osmotic control L-glucose (L-Glc) or with Thiamet-G or its vehicle control (H2O) followed by the addition of TNF-alpha or vehicle (H2O) for 21 h. After incubation, rings were mounted in a myograph to assess arterial reactivity. Twenty-four hours of incubation of aortic rings with TNF-alpha resulted in 1) a hypocontractility to 60 mM K+ solution and phenylephrine, 2) blunted endothelium-dependent relaxation responses to ACh and substance P, and 3) unaltered relaxing response to the Ca2+ ionophore A-23187 and the NO donor sodium nitroprusside compared with aortic rings cultured in the absence of TNF-alpha. D-GlcN and Thiamet-G pretreatment suppressed the TNF-alpha-induced hypocontractility and endothelial dysfunction. Total protein O-GlcNAc levels were significantly higher in aortic segments treated with D-GlcN or Thiamet-G compared with controls. Expression of iNOS protein was increased in TNF-alpha-treated rings, and this was attenuated by pretreatment with either D-GlcN or Thiamet-G. Dense immunostaining for nitrotyrosylated proteins was detected in the endothelium and media of the aortic wall, suggesting enhanced peroxynitrite production by iNOS. These findings demonstrate that acute increases in protein O-GlcNAcylation prevent TNF-alpha-induced vascular dysfunction, at least in part, via suppression of iNOS expression.