title: Sirtuin 1-mediated cellular metabolic memory of high glucose via the LKB1/AMPK/ROS pathway and therapeutic effects of metformin.
abstract: Cellular metabolic memory occurs in diabetic microvascular and macrovascular complications, but the underlying mechanisms remain unclear. Here, we investigate the role of sirtuin 1 (SIRT1) and metformin in this phenomenon. In bovine retinal capillary endothelial cells (BRECs) and retinas of diabetic rats, the inflammatory gene, nuclear factor-κB (NF-κB), and the proapoptotic gene, Bax, induced by hyperglycemia, remained elevated after returning to normoglycemia. BRECs with small interfering RNA-mediated SIRT1 knockdown had increased sensitivity to hyperglycemia stress, whereas SIRT1 overexpression or activation by metformin inhibited the increase of mitochondrial reactive oxygen species-mediated glyceraldehyde-3-phosphate dehydrogenase by poly (ADP-ribose) polymerase (PARP) activity through the upregulation of liver kinase B1/AMP-activated protein kinase (LKB1/AMPK), ultimately suppressing NF-κB and Bax expression. Furthermore, we showed that hyperglycemia led to PARP activation, which in turn may have downregulated SIRT1. Of importance, this study also demonstrated that metformin suppressed the "memory" of hyperglycemia stress in the diabetic retinas, which may be involved in the SIRT1/LKB1/AMPK pathway. Our data suggest that SIRT1 is a potential therapeutic target for the treatment of the cellular metabolic memory, and the use of metformin specifically for such therapy may be a new avenue of investigation in the diabetes field.
authors: Department of Ophthalmology, First People's Hospital of Shanghai, Shanghai Jiaotong University, Shanghai, China. zzheng88@sjtu.edu.cn
authors: Zhi
authors: Z
authors: Zheng
authors: Haibing
authors: H
authors: Chen
authors: Jun
authors: J
authors: Li
authors: Tao
authors: T
authors: Li
authors: Bingqing
authors: B
authors: Zheng
authors: Ying
authors: Y
authors: Zheng
authors: Huiyi
authors: H
authors: Jin
authors: Ying
authors: Y
authors: He
authors: Qing
authors: Q
authors: Gu
authors: Xun
authors: X
authors: Xu
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000263:Adenylate Kinase / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000235:genetics*; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D016328:NF-kappa B / Q000378:metabolism; D009994:Osmolar Concentration; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism* / Q000494:pharmacology; D012160:Retina / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D008687:Metformin; D017346:Protein Serine-Threonine Kinases; C488755:Stk11 protein, rat; D000091162:AMP-Activated Protein Kinase Kinases; D000263:Adenylate Kinase; D056564:Sirtuin 1