SIRT6 protects against endothelial dysfunction and atherosclerosis in mice.
SIRT6 protects against endothelial dysfunction and atherosclerosis in mice.
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DOI：
10.18632/aging.100975
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发表时间：
2016-05
期刊：
影响因子：
--
通讯作者：
Jin ZG
中科院分区：
文献类型：
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作者：
Xu S;Yin M;Koroleva M;Mastrangelo MA;Zhang W;Bai P;Little PJ;Jin ZG
SIRT 6是sirtuin家族的重要成员，抑制炎症、衰老和DNA损伤，其中三个是导致内皮功能障碍的因素。在ApoE−/−小鼠和人类患者的动脉粥样硬化病变中，SIRT 6表达降低。然而，SIRT 6在调节血管内皮功能和动脉粥样硬化中的作用尚不清楚。在这里，我们表明SIRT 6可以防止内皮功能障碍和动脉粥样硬化。整体和内皮特异性SIRT 6敲除小鼠表现出受损的内皮依赖性血管舒张。此外，喂食高脂饮食（HFD）的SIRT 6 +/−单倍不足小鼠也表现出内皮依赖性血管舒张受损。重要的是，SIRT 6 +/−;喂食HFD后的ApoE−/−小鼠表现出动脉粥样硬化病变发展加剧，同时促炎细胞因子VCAM-1表达增加。在培养的人内皮细胞（EC）中的SIRT 6功能的丧失和获得的研究表明，SIRT 6减弱单核细胞对EC的粘附。RNA测序分析显示，SIRT 6过表达降低了多种动脉粥样硬化相关基因的表达，包括致动脉粥样硬化基因TNFSF 4（肿瘤坏死因子超家族成员4）。染色质免疫沉淀分析表明，SIRT 6通过结合并脱乙酰化TNFSF 4基因启动子处的H3 K9来降低TNFSF 4基因的表达。总的来说，这些研究结果表明，SIRT 6在维持内皮功能方面发挥着关键作用，增加SIRT 6活性可能是对抗动脉粥样硬化疾病的新治疗策略。
SIRT6 is an important member of sirtuin family that represses inflammation, aging and DNA damage, three of which are causing factors for endothelial dysfunction. SIRT6 expression is decreased in atherosclerotic lesions from ApoE−/− mice and human patients. However, the role of SIRT6 in regulating vascular endothelial function and atherosclerosis is not well understood. Here we show that SIRT6 protects against endothelial dysfunction and atherosclerosis. Global and endothelium-specific SIRT6 knockout mice exhibited impaired endothelium-dependent vasorelaxation. Moreover, SIRT6+/− haploinsufficient mice fed a high-fat diet (HFD) also displayed impaired endothelium-dependent vasorelaxation. Importantly, SIRT6+/−;ApoE−/− mice after HFD feeding exhibited exacerbated atherosclerotic lesion development, concurrent with increased expression of the proinflammatory cytokine VCAM-1. Loss- and gain-of-SIRT6 function studies in cultured human endothelial cells (ECs) showed that SIRT6 attenuated monocyte adhesion to ECs. RNA-sequencing profiling revealed that SIRT6 overexpression decreased the expression of multiple atherosclerosis-related genes, including proatherogenic gene TNFSF4 (tumor necrosis factor superfamily member 4). Chromatin immunoprecipitation assays showed that SIRT6 decreased TNFSF4 gene expression by binding to and deacetylating H3K9 at TNFSF4 gene promoter. Collectively, these findings demonstrate that SIRT6 play a pivotal role in maintaining endothelial function and increased SIRT6 activity could be a new therapeutic strategy to combat atherosclerotic disease.