Activation of IKKβ by glucose is necessary and sufficient to impair insulin signaling and nitric oxide production in endothelial cells
Activation of IKKβ by glucose is necessary and sufficient to impair insulin signaling and nitric oxide production in endothelial cells
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DOI：
10.1016/j.yjmcc.2005.05.009
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发表时间：
2005-08-01
影响因子：
5
通讯作者：
Schwartz, MW
中科院分区：
文献类型：
--
作者：
Kim, F;Tysseling, KA;Schwartz, MW
高血糖对内皮细胞产生一氧化氮（NO）的损害与糖尿病增加心血管疾病风险的作用有关，但这种作用的分子基础尚不清楚。在骨骼肌中，糖尿病诱导抑制剂kappaB激酶（IKK β）的激活，IKK β是对炎症刺激反应的关键细胞介质，这会损害通过胰岛素受体底物-磷脂酰肌醇3-OH激酶（IRS-1/PI 3-激酶）途径的胰岛素信号转导。由于内皮型一氧化氮合酶（eNOS）的激活依赖于IRS-1/PI 3-激酶信号，我们假设IKK β的激活可能有助于葡萄糖损害NO产生的作用。在这里，我们发现，牛主动脉内皮细胞暴露于高糖（25 mM）24小时损害胰岛素介导的IRS-1酪氨酸磷酸化，Akt丝氨酸磷酸化，eNOS激活和NO产生。高糖处理也激活IKK β，并预先用阿司匹林，IKK β的药理学抑制剂，阻止葡萄糖诱导的IKK β激活和高糖损害胰岛素介导的NO产生的作用。这些对葡萄糖的不良反应也可通过选择性抑制IKK β信号传导来阻断，该信号传导通过过表达激酶失活形式的酶来实现。相反，野生型IKK β的过度表达再现了高糖对胰岛素介导的eNOS活化的有害作用。这些数据表明，IKK β的激活在介导高糖对内皮细胞功能的有害作用中起着关键和新颖的作用。(c)2005爱思唯尔有限公司保留所有权利。
Hyperglycemic impairment of nitric oxide (NO) production by endothelial cells is implicated in the effect of diabetes to increase cardiovascular disease risk, but the molecular basis for this effect is unknown. In skeletal muscle, diabetes induces activation of inhibitor kappaB kinase (IKK beta), a key cellular mediator of the response to inflammatory stimuli, and this impairs insulin signal transduction via the insulin receptor substrate-phosphatidylinositol 3-OH kinase (IRS-1/PI3-kinase) pathway. Since activation of endothelial nitric oxide synthase (eNOS) is dependent on IRS-1/PI3-kinase signaling, we hypothesized that activation of IKK beta may contribute to the effect of glucose to impair NO production. Here, we show that exposure of bovine aortic endothelial cells to high glucose (25 mM) for 24 h impaired insulin-mediated tyrosine phosphorylation of IRS-1, serine phosphorylation of Akt, activation of eNOS, and production of NO. High glucose treatment also activated IKK beta, and pretreatment with aspirin, a pharmacological inhibitor of IKK beta, prevented both glucose-induced IKK beta activation and the effect of high glucose to impair insulin-mediated NO production. These adverse responses to glucose were also blocked by selective inhibition of IKK beta signaling via overexpression of a kinase-inactive form of the enzyme. Conversely, overexpression of wild-type IKK beta recapitulated the deleterious effect of high glucose on insulin-mediated activation of eNOS. These data demonstrate that activation of IKK beta plays a critical and novel role to mediate the deleterious effects of high glucose on endothelial cell function. (c) 2005 Elsevier Ltd. All rights reserved.