title: Metformin and Resveratrol Inhibited High Glucose-Induced Metabolic Memory of Endothelial Senescence through SIRT1/p300/p53/p21 Pathway.
abstract: 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."
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Cardiovascular Institute, Fuwai Hospital, and National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Erli
authors.initials: E
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Cardiovascular Institute, Fuwai Hospital, and National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Qianyun
authors.initials: Q
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Cardiovascular Institute, Fuwai Hospital, and National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Cardiovascular Institute, Fuwai Hospital, and National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Ruixia
authors.initials: R
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Cardiovascular Institute, Fuwai Hospital, and National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Siyong
authors.initials: S
authors.lastname: Teng
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Cardiovascular Institute, Fuwai Hospital, and National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Yongjian
authors.initials: Y
authors.lastname: Wu
mesh_terms: D016922:Cellular Senescence / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects*; D056564:Sirtuin 1 / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D013267:Stilbenes; D016159:Tumor Suppressor Protein p53; D008687:Metformin; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D056564:Sirtuin 1; D005947:Glucose; D000077185:Resveratrol