Zhao Ying, Jia Xiong, Yang Xiaoyan, Bai Xiangli, Lu Yajing, Zhu Lin, Cheng Wenzhuo, Shu Meng, Zhu Yan, Du Xiaolong, Wang Li, Shu Yan, Song Yi, Jin Si
Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430077, China.
Department of Pharmacology, the Key Laboratory of Drug Target Researches and Pharmacodynamics Evaluation of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
Metabolism. 2022 Jun;131:155162. doi: 10.1016/j.metabol.2022.155162. Epub 2022 Feb 12.
Atherosclerosis (AS) is the basis of diabetic macrovascular complications. The plasma low-density lipoprotein (LDL) particles transcytosis across endothelial cells (ECs) and deposition under the endothelium is the initiation step of AS. We previously reported that high glucose inhibits the autophagic degradation of Caveolin-1 and promote LDL transcytosis across ECs, which in turn accelerates atherosclerotic progression. Since Sirt6 is a chromatin-associated protein with deacetylation activity, whether it can regulate Caveolin-1 acetylation and regulating the autophagic degradation of Caveolin-1 remains elusive.
Autophagy and histone acetylation were assessed in the umbilical cords of patients with gestational diabetes mellitus (GDM) by immunohistochemistry. An in vitro model of LDL transcytosis was established, and the role of Sirt6 in LDL transcytosis across endothelial cells was clarified. The effect of Sirt6 on the autophagic degradation of Caveolin-1 under hyperglycemic conditions was explored in a streptozotocin (STZ)-induced diabetic AS model established using the ApoE mice.
Caveolin-1 and acetylated histone H3 levels were significantly increased, while LC3B and Sirt6 were downregulated in the monolayer of the vascular wall from GDM and type 2 diabetes mellitus (T2DM) patients. Immunoprecipitation assays showed that Sirt6 interacts with Caveolin-1 and specifically mediated its acetylation levels. Immuno-electron microscopy (EM) further indicated that Sirt6 overexpression triggered the autophagic lysosomal degradation of Caveolin-1. ECs-specific overexpression of Sirt6 by adeno-associated viral vector serotype 9 (AAV9) induced autophagy, reduced Caveolin-1 expression, and ameliorated atherosclerotic plaque formation in STZ-induced diabetic ApoE mice.
Sirt6-mediated acetylation of Caveolin-1 activates its autophagic degradation and inhibits high glucose-stimulated LDL transcytosis. Thus, the Sirt6/Caveolin-1 autophagic pathway plays a crucial role in diabetic AS, and the overexpression or activation of Sirt6 is a novel therapeutic strategy.
动脉粥样硬化（AS）是糖尿病大血管并发症的基础。血浆低密度脂蛋白（LDL）颗粒经内皮细胞（ECs）转胞吞作用并在内皮下沉积是AS的起始步骤。我们之前报道过高糖抑制小窝蛋白-1（Caveolin-1）的自噬降解并促进LDL经ECs的转胞吞作用，进而加速动脉粥样硬化进展。由于沉默调节蛋白6（Sirt6）是一种具有去乙酰化活性的染色质相关蛋白，它是否能调节Caveolin-1的乙酰化并调控Caveolin-1的自噬降解仍不清楚。
通过免疫组织化学评估妊娠期糖尿病（GDM）患者脐带中的自噬和组蛋白乙酰化。建立LDL转胞吞作用的体外模型，阐明Sirt6在内皮细胞LDL转胞吞作用中的作用。在使用载脂蛋白E（ApoE）小鼠建立的链脲佐菌素（STZ）诱导的糖尿病AS模型中，探究Sirt6在高糖条件下对Caveolin-1自噬降解的影响。
在GDM和2型糖尿病（T2DM）患者的血管壁单层中，Caveolin-1和乙酰化组蛋白H3水平显著升高，而微管相关蛋白1轻链3β（LC3B）和Sirt6下调。免疫沉淀试验表明，Sirt6与Caveolin-1相互作用并特异性介导其乙酰化水平。免疫电子显微镜（EM）进一步表明，Sirt6过表达触发Caveolin-1的自噬溶酶体降解。通过9型腺相关病毒载体（AAV9）在ECs中特异性过表达Sirt6可诱导自噬，降低Caveolin-1表达，并改善STZ诱导的糖尿病ApoE小鼠的动脉粥样硬化斑块形成。
Sirt6介导的Caveolin-1乙酰化激活其自噬降解并抑制高糖刺激的LDL转胞吞作用。因此，Sirt6/Caveolin-1自噬途径在糖尿病AS中起关键作用，Sirt6的过表达或激活是一种新的治疗策略。
