SIRT3 Deficiency Induces Endothelial Insulin Resistance and Blunts Endothelial-Dependent Vasorelaxation in Mice and Human with Obesity.
SIRT3 Deficiency Induces Endothelial Insulin Resistance and Blunts Endothelial-Dependent Vasorelaxation in Mice and Human with Obesity.
复制标题
SIRT3 缺乏会诱导肥胖小鼠和人类的内皮胰岛素抵抗并减弱内皮依赖性血管舒张作用
DOI：
10.1038/srep23366
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发表时间：
2016-03-22
影响因子：
4.6
通讯作者：
Gao F
中科院分区：
文献类型：
--
作者：
Yang L;Zhang J;Xing W;Zhang X;Xu J;Zhang H;Chen L;Ning X;Ji G;Li J;Zhao Q;Gao F
最近的证据表明Sirtuin 3 （SIRT3）在许多代谢性疾病的发展中起着关键作用，但SIRT3对血管稳态的贡献在很大程度上仍然未知。本研究的目的是探讨SIRT3在肥胖患者内皮胰岛素抵抗和血管功能障碍中的作用。我们发现，与非肥胖者相比，病态肥胖者的胰岛素诱导的肠系膜血管松弛受损，并伴有血管SIRT3表达降低。体外培养的人内皮细胞中SIRT3的下调增加了线粒体活性氧（mtROS）和胰岛素信号通路受损，Akt和内皮型一氧化氮合酶磷酸化降低，随后一氧化氮（NO）释放减少。此外，24周高脂饮食（HFD）诱导的肥胖小鼠对胰岛素和乙酰胆碱的内皮依赖性血管松弛功能受损，sirt3基因缺失进一步加剧了这种情况。清除mtROS不仅可以恢复SIRT3敲除细胞中胰岛素刺激的NO生成，还可以改善胰岛素诱导的SIRT3敲除小鼠的血管松弛。综上所述，我们的研究结果表明SIRT3积极调节内皮胰岛素敏感性，并表明SIRT3缺乏和由此导致的mtROS增加有助于肥胖的血管功能障碍。
Recent evidence implicates the critical role of Sirtuin 3 (SIRT3) in the development of many metabolic diseases, but the contribution of SIRT3 to vascular homeostasis remains largely unknown. The aim of this study was to investigate the role of SIRT3 in endothelial insulin resistance and vascular dysfunction in obesity. We found an impaired insulin-induced mesenteric vasorelaxation and concomitant reduced vascular SIRT3 expression in morbid obese human subjects compared with the non-obese subjects. Downregulation of SIRT3 in cultured human endothelial cells increased mitochondrial reactive oxygen species (mtROS) and impaired insulin signaling as evidenced by decreased phosphorylation of Akt and endothelial nitric oxide synthase and subsequent reduced nitric oxide (NO) release. In addition, obese mice induced by 24-week high-fat diet (HFD) displayed an impaired endothelium-dependent vasorelaxation to both insulin and acetylcholine, which was further exacerbated by the gene deletion ofSirt3. Scavenging of mtROS not only restored insulin-stimulated NO production in SIRT3 knockdown cells, but also improved insulin-induced vasorelaxation in SIRT3 knockout mice fed with HFD. Taken together, our findings suggest that SIRT3 positively regulates endothelial insulin sensitivity and show that SIRT3 deficiency and resultant increased mtROS contribute to vascular dysfunction in obesity.