Resveratrol Promotes Diabetic Wound Healing via SIRT1-FOXO1-c-Myc Signaling Pathway-Mediated Angiogenesis
Resveratrol Promotes Diabetic Wound Healing via SIRT1-FOXO1-c-Myc Signaling Pathway-Mediated Angiogenesis
复制标题
白藜芦醇通过 SIRT1-FOXO1-c-Myc 信号通路介导的血管生成促进糖尿病伤口愈合
DOI：
10.3389/fphar.2019.00421
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发表时间：
2019-04-24
影响因子：
5.6
通讯作者：
Zhu, Zhongxin
中科院分区：
文献类型：
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作者：
Huang, Xiaozhong;Sun, Jia;Zhu, Zhongxin
背景/目标：糖尿病性皮肤溃疡是临床上的一个严重挑战，其中高血糖引起的血管生成障碍和内皮功能障碍起着至关重要的作用。白藜芦醇（Resveratrol，RES）是一种沉默信息调节因子1（Silent Information Regulator 1，SIRT 1）激动剂，具有改善内皮功能和促血管生成的作用，已成为糖尿病皮肤溃疡治疗的研究热点，但RES调节这些过程的机制尚不清楚。因此，本研究旨在确定RES是否通过减轻高血糖诱导的内皮功能障碍和血管生成障碍在糖尿病伤口愈合中发挥其观察到的保护作用。我们研究了RES对细胞迁移、细胞增殖、细胞凋亡、管形成，以及通过半定量RT-PCR，蛋白质印迹分析，末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）染色和体外免疫荧光。通过TUNEL染色、免疫荧光和活体照相进一步探讨RES对db/db小鼠内皮功能障碍和伤口愈合障碍的作用。结果：RES能明显抑制高血糖引发的内皮功能障碍和血管生成障碍，沿着恢复高血糖损伤的SIRT 1信号通路活性，促进糖尿病伤口愈合。用SIRT 1抑制剂EX-527预处理，取消RES介导的内皮保护和促血管生成作用，然后延迟糖尿病伤口愈合。此外，在HUVECs和db/db小鼠中检查SIRT 1的转录因子底物forkhead box O 1（FOXO 1）的过表达，发现RES激活SIRT 1以恢复高血糖引发的内皮功能障碍和血管生成障碍，然后以c-Myc依赖的方式促进糖尿病伤口愈合。预处理与10058-F4，一个c-Myc抑制剂，抑制RES介导的内皮保护，血管生成，和糖尿病wound healing.Conclusion：我们的研究结果表明，在糖尿病伤口愈合RES的积极作用，通过其SIRT 1依赖的内皮保护和促血管生成的影响涉及FOXO 1的抑制和c-Myc表达的去抑制。
Background/Aims: Diabetic non-healing skin ulcers represent a serious challenge in clinical practice, in which the hyperglycemia-induced disturbance of angiogenesis, and endothelial dysfunction play a crucial role. Resveratrol (RES), a silent information regulator 1 (SIRT1) agonist, can improve endothelial function and has strong proangiogenic properties, and has thus become a research focus for the treatment of diabetic non-healing skin ulcers; however, the underlying mechanism by which RES regulates these processes remains unclear. Therefore, the present study was intended to determine if RES exerts its observed protective role in diabetic wound healing by alleviating hyperglycemia-induced endothelial dysfunction and the disturbance of angiogenesis.Methods: We investigated the effects of RES on cell migration, cell proliferation, apoptosis, tube formation, and the underlying molecular mechanisms in 33 mM high glucose-stimulated human umbilical vein endothelial cells (HUVECs) by semi-quantitative RT-PCR, western blot analysis, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and immunofluorescence in vitro. We further explored the role of RES on endothelial dysfunction and wound healing disturbance in db/db mice by TUNEL staining, immunofluorescence, and photography in vivo.Results: We observed an obvious inhibition of hyperglycemia-triggered endothelial dysfunction and a disturbance of angiogenesis, followed by the promotion of diabetic wound healing via RES, along with restoration of the activity of the hyperglycemia-impaired SIRT1 signaling pathway. Pretreatment with EX-527, a SIRT1 inhibitor, abolished the RES-mediated endothelial protection and pro-angiogenesis action, and then delayed diabetic wound healing. Furthermore, examination of the overexpression of forkhead box O1 (FOXO1), a transcription factor substrate of SIRT1, in HUVECs and db/db mice revealed that RES activated SIRT1 to restore hyperglycemia-triggered endothelial dysfunction and disturbance of angiogenesis, followed by the promotion of diabetic wound healing in a c-Myc-dependent manner. Pretreatment with 10058-F4, a c-Myc inhibitor, repressed RES-mediated endothelial protection, angiogenesis, and diabetic wound healing.Conclusion: Our findings indicate that the positive role of RES in diabetic wound healing via its SIRT1-dependent endothelial protection and pro-angiogenic effects involves the inhibition of FOXO1 and the de-repression of c-Myc expression.