Insulin generates free radicals in human fibroblasts ex vivo by a protein kinase C-dependent mechanism, which is inhibited by pravastatin
Insulin generates free radicals in human fibroblasts ex vivo by a protein kinase C-dependent mechanism, which is inhibited by pravastatin
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DOI：
10.1016/j.freeradbiomed.2006.04.015
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发表时间：
2006-08-01
影响因子：
7.4
通讯作者：
Semplicini, Andrea
中科院分区：
文献类型：
--
作者：
Ceolotto, Giulio;Papparella, Italia;Semplicini, Andrea
胰岛素能产生氧自由基。他汀类药物，3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂，发挥强大的抗氧化作用。本研究旨在阐明胰岛素产生自由基的机制，并评估普伐他汀是否调节这种作用。在暴露于高胰岛素浓度的人志愿者培养的皮肤成纤维细胞中，无论是否存在普伐他汀，胰岛素诱导NAD（P）H氧化酶的p47（phox）亚基从细胞质易位到膜，并通过PKC δ依赖性机制产生自由基氧物种。胰岛素诱导的p47（phox）易位是PKC δ依赖性的，并被普伐他汀减弱，但不依赖于Akt和Rac 1的激活。胰岛素诱导的Akt磷酸化增加普伐他汀和ERK 1/2磷酸化减弱。本研究证明了一种新的机制，胰岛素刺激产生的自由基在人成纤维细胞，离体。它涉及磷脂酰肌醇3-激酶、PKC δ和p47（phox）易位并促进ERK 1/2磷酸化。普伐他汀通过抑制PKC 6抑制自由基氧自由基的产生。这些观察结果为普伐他汀治疗胰岛素抵抗综合征患者的积极作用提供了有力的解释。(c)2006年爱思唯尔公司All rights reserved.
Insulin can generate oxygen free radicals. Statins, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, exert a powerful antioxidant effect. The present study aimed to clarify the mechanisms through which insulin generates free radicals and to assess whether pravastatin modulazes such effects. In cultured skin fibroblasts from human volunteers exposed to high insulin concentration, either in the presence or in the absence of pravastatin, insulin induced translocation of the p47(phox) subunit of NAD(P)H oxidase from the cytosol to the membrane and generation of radical oxygen species through a PKC delta-dependent mechanism. The insulin-induced translocation of p47(phox) was PKC delta dependent and attenuated by pravastatin, but independent of the activation of Akt and Rac1. Insulin-induced Akt phosphorylation was increased by pravastatin and ERK1/2 phosphorylation attenuated. The present study demonstrates a novel mechanism by which insulin stimulates the generation of free radicals in human fibroblasts, ex vivo. It involves phosphatidylinositol 3-kinase, PKC delta, and p47(phox) translocation and promotes ERK1/2 phosphorylation. Pravastatin inhibited radical oxygen species production by inhibiting PKC 6. These observations offer a robust explanation for the positive effects of pravastatin treatment in patients with insulin resistance syndrome. (c) 2006 Elsevier Inc. All rights reserved.