Ski promotes proliferation and inhibits apoptosis in fibroblasts under high-glucose conditions via the FoxO1 pathway.
Ski promotes proliferation and inhibits apoptosis in fibroblasts under high-glucose conditions via the FoxO1 pathway.
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Ski 通过 FoxO1 途径促进高糖条件下成纤维细胞增殖并抑制细胞凋亡
DOI：
10.1111/cpr.12971
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发表时间：
2021-03
影响因子：
8.5
通讯作者：
Li P
中科院分区：
文献类型：
--
作者：
Peng Y;Xiong RP;Zhang ZH;Ning YL;Zhao Y;Tan SW;Zhou YG;Li P
本研究阐明了Ski在高糖（HG）条件下调节成纤维细胞增殖和凋亡中的作用和信号通路。采用EdU掺入法和TUNEL法观察大鼠原代成纤维细胞的增殖和凋亡情况。免疫荧光染色和Western blotting检测相应因子的蛋白和磷酸化水平。免疫沉淀法测定Ski与fox01或Ski与HDAC1的相互作用。通过重组腺病毒转染过表达Ski蛋白，利用靶向小干扰RNA敲低FoxO1和HDAC1。本研究发现，HG抑制大鼠原代成纤维细胞增殖，增加细胞凋亡，降低Ski水平。相反，升高的Ski蛋白水平可减轻HG诱导的增殖抑制和细胞凋亡促进。升高的Ski蛋白水平也增加了Ski与FoxO1的结合，从而降低FoxO1的乙酰化，并且干扰FoxO1导致Ski在HG下成纤维细胞中的调节作用丧失。升高的Ski蛋白水平通过HDAC1介导的去乙酰化降低FoxO1的乙酰化。因此，这些发现首次证实了HG条件下Ski通过FoxO1通路调节成纤维细胞增殖和凋亡。在HG条件下，fox01乙酰化水平升高。FoxO1作为一种转录因子，参与诱导调控细胞增殖或凋亡等的特殊基因亚群。升高的Ski蛋白增加了Ski与FoxO1的结合，从而通过Ski与HDAC1结合介导去乙酰化，导致FoxO1乙酰化水平降低。因此，fox01转录因子的作用被抑制。
The present study clarified the role and signalling pathway of Ski in regulating proliferation and apoptosis in fibroblasts under high‐glucose (HG) conditions. The proliferation and apoptosis of rat primary fibroblasts were assessed using EdU incorporation and TUNEL assays. The protein and phosphorylation levels of the corresponding factors were measured using immunofluorescence staining and Western blotting. Immunoprecipitation was used to determine the interactions between Ski and FoxO1 or Ski and HDAC1. The Ski protein was overexpressed via recombinant adenovirus transfection, and FoxO1 and HDAC1 were knocked down using targeted small‐interfering RNA. The present study found that HG inhibited fibroblast proliferation, increased apoptosis and reduced Ski levels in rat primary fibroblasts. Conversely, increasing Ski protein levels alleviated HG‐induced proliferation inhibition and apoptosis promotion. Increasing Ski protein levels also increased Ski binding to FoxO1 to decrease FoxO1 acetylation, and interfering with FoxO1 caused loss of the regulatory effect of Ski in fibroblasts under HG. Increasing Ski protein levels decreased FoxO1 acetylation via HDAC1‐mediated deacetylation. Therefore, these findings confirmed for the first time that Ski regulated fibroblast proliferation and apoptosis under HG conditions via the FoxO1 pathway. Under HG conditions, FoxO1 acetylation level was increased. As a transcription factor, FoxO1 involved in the induction of a special subset of genes that regulate cellular proliferation or apoptosis, etc Increased Ski protein increased the binding of Ski to FoxO1, which mediated deacetylation through Ski binding with HDAC1 and resulted in a reduction in FoxO1 acetylation level. Therefore, the role of FoxO1 transcription factor was inhibited.
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