Metformin and Resveratrol Inhibited High Glucose-Induced Metabolic Memory of Endothelial Senescence through SIRT1/p300/p53/p21 Pathway.
Metformin and Resveratrol Inhibited High Glucose-Induced Metabolic Memory of Endothelial Senescence through SIRT1/p300/p53/p21 Pathway.
复制标题
二甲双胍和白藜芦醇通过 SIRT1/p300/p53/p21 通路抑制高血糖诱导的内皮衰老代谢记忆
DOI：
10.1371/journal.pone.0143814
复制
发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Wu Y
中科院分区：
文献类型：
--
作者：
Zhang E;Guo Q;Gao H;Xu R;Teng S;Wu Y
内皮细胞衰老在糖尿病血管并发症中起重要作用。最近的证据表明，短暂的高血糖可能会加剧持续的糖尿病血管并发症，这种现象被称为“代谢记忆”。虽然SIRT 1已被证明介导高葡萄糖诱导的内皮衰老，但“代谢记忆”是否以及如何通过SIRT 1信号传导影响内皮衰老仍然是未知的。在这项研究中，我们研究了SIRT 1轴的参与以及白藜芦醇（RSV）和二甲双胍（MET），两种有效的SIRT 1激活剂，在细胞衰老的“代谢记忆”（衰老“记忆”）的发生过程中的保护作用。将人脐血管内皮细胞（HUVEC）在正常葡萄糖（NG）/高葡萄糖（HG）培养基中培养6天，或在有或没有RSV或MET处理的情况下培养3天HG接着3天NG（HN）。研究表明，HN孵育引发了去乙酰化酶SIRT 1的持续下调和乙酰转移酶p300的上调，导致持续的过度乙酰化（在K382）和p53的激活，以及随后的p53/p21介导的衰老“记忆”。相反，衰老的“记忆”被废除SIRT 1的过度表达或敲低p300。有趣的是，我们发现SIRT 1和p300可以在HN刺激下相互调节，这表明乙酰转移酶和脱乙酰酶之间的微妙平衡可能对非组蛋白蛋白（如p53）的持续乙酰化和激活以及最终发生“代谢记忆”特别重要。此外，我们发现RSV或MET处理通过调节SIRT 1/p300/p53/p21通路来防止衰老的“记忆”。值得注意的是，MET而不是RSV的早期和连续治疗对于预防衰老的“记忆”特别重要。短期高糖刺激可通过SIRT 1/p300/p53/p21途径诱导内皮细胞持续衰老。RVS或MET处理可以增强SIRT 1介导的信号传导，从而保护免受衰老的“记忆”，而不依赖于它们的降糖机制。因此，它们可能作为有前途的治疗药物，对发展的“代谢记忆”。
Endothelial senescence plays crucial roles in diabetic vascular complication. Recent evidence indicated that transient hyperglycaemia could potentiate persistent diabetic vascular complications, a phenomenon known as “metabolic memory.” Although SIRT1 has been demonstrated to mediate high glucose-induced endothelial senescence, whether and how “metabolic memory” would affect endothelial senescence through SIRT1 signaling remains largely unknown. In this study, we investigated the involvement of SIRT1 axis as well as the protective effects of resveratrol (RSV) and metformin (MET), two potent SIRT1 activators, during the occurrence of “metabolic memory” of cellular senescence (senescent “memory”). Human umbilical vascular endothelial cells (HUVECs) were cultured in either normal glucose (NG)/high glucose (HG) media for 6 days, or 3 days of HG followed by 3 days of NG (HN), with or without RSV or MET treatment. It was shown that HN incubation triggered persistent downregulation of deacetylase SIRT1 and upregulation of acetyltransferase p300, leading to sustained hyperacetylation (at K382) and activation of p53, and subsequent p53/p21-mediated senescent “memory.” In contrast, senescent “memory” was abrogated by overexpression of SIRT1 or knockdown of p300. Interestingly, we found that SIRT1 and p300 could regulate each other in response to HN stimulation, suggesting that a delicate balance between acetyltransferases and deacetylases may be particularly important for sustained acetylation and activation of non-histone proteins (such as p53), and eventually the occurrence of “metabolic memory.” Furthermore, we found that RSV or MET treatment prevented senescent “memory” by modulating SIRT1/p300/p53/p21 pathway. Notably, early and continuous treatment of MET, but not RSV, was particularly important for preventing senescent “memory.” In conclusion, short-term high glucose stimulation could induce sustained endothelial senescence via SIRT1/p300/p53/p21 pathway. RVS or MET treatment could enhance SIRT1-mediated signaling and thus protect against senescent “memory” independent of their glucose lowering mechanisms. Therefore, they may serve as promising therapeutic drugs against the development of “metabolic memory.”