TRIB3 r84 variant is associated with impaired insulin-mediated nitric oxide production in human endothelial cells
TRIB3 r84 variant is associated with impaired insulin-mediated nitric oxide production in human endothelial cells
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DOI：
10.1161/atvbaha.108.162883
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发表时间：
2008-07-01
影响因子：
8.7
通讯作者：
Sesti, Giorgio
中科院分区：
文献类型：
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作者：
Andreozzi, Francesco;Formoso, Gloria;Sesti, Giorgio
背景-在内皮中，胰岛素通过胰岛素受体/IRS-1/PI 3-激酶/Akt/eNOS信号通路促进一氧化氮（NO）的产生。最近已经鉴定了胰岛素作用的抑制剂TRIB 3，其通过结合并抑制Akt磷酸化来影响胰岛素作用。我们最近描述了一个Q84 R获得的功能多态性TRIB 3与R84变异与胰岛素抵抗和较早的年龄在myocardial infarction.Methods和Results-To调查TRIB 3 R84变异对内皮胰岛素作用的影响，我们培养的人脐静脉内皮细胞（HUVEC）自然携带不同的TRIB 3基因型（QQ-，QR-，或RR-HUVEC）。TRIB 3对胰岛素刺激的Akt磷酸化的抑制活性和与Akt免疫共沉淀的蛋白质的量在QR-和RR-中比在QQ-HUVEC中显著更大。胰岛素刺激后，QR-和RR-的Akt和eNOS活化以及NO产生均显著低于QQ- HUVECs。TRIB 3分子建模分析提供了深入了解的结构变化的多态性可能决定蛋白质-蛋白质相互作用与Akt.Conclusions-Our数据表明，TRIB 3 R84变异损害胰岛素信号和NO生产在人内皮细胞的差异。这一发现为TRIB 3 R84对冠状动脉疾病遗传易感性的有害作用提供了合理的生物学背景。
Background-In the endothelium, insulin promotes nitric oxide (NO) production, through the insulin receptor/IRS-1/PI3-Kinase/Akt/eNOS signaling pathway. An inhibitor of insulin action, TRIB3, has recently been identified which affects insulin action by binding to and inhibiting Akt phosphorylation. We have recently described a Q84R gain-of-function polymorphism of TRIB3 with the R84 variant being associated with insulin resistance and an earlier age at myocardial infarction.Methods and Results-To investigate the TRIB3 R84 variant impact on endothelial insulin action, we cultured human umbilical vein endothelial cells (HUVECs) naturally carrying different TRIB3 genotypes (QQ-, QR-, or RR-HUVECs). TRIB3 inhibitory activity on insulin-stimulated Akt phosphorylation and the amount of protein which was coimmunoprecipitable with Akt were significantly greater in QR- and RR- as compared to QQ- HUVECs. After insulin stimulation, Akt and eNOS activation as well as NO production were markedly decreased in QR- and RR- as compared to QQ- HUVECs. TRIB3 molecular modeling analysis provided insights into the structural changes related to the polymorphisms potentially determining differences in protein-protein interaction with Akt.Conclusions-Our data demonstrate that the TRIB3 R84 variant impairs insulin signaling and NO production in human endothelial cells. This finding provides a plausible biological background for the deleterious role of TRIB3 R84 on genetic susceptibility to coronary artery disease.