title: Oxidative stress induces endothelial cell senescence via downregulation of Sirt6.
abstract: Accumulating evidence has shown that diabetes accelerates aging and endothelial cell senescence is involved in the pathogenesis of diabetic vascular complications, including diabetic retinopathy. Oxidative stress is recognized as a key factor in the induction of endothelial senescence and diabetic retinopathy. However, specific mechanisms involved in oxidative stress-induced endothelial senescence have not been elucidated. We hypothesized that Sirt6, which is a nuclear, chromatin-bound protein critically involved in many pathophysiologic processes such as aging and inflammation, may have a role in oxidative stress-induced vascular cell senescence. Measurement of Sirt6 expression in human endothelial cells revealed that H2O2 treatment significantly reduced Sirt6 protein. The loss of Sirt6 was associated with an induction of a senescence phenotype in endothelial cells, including decreased cell growth, proliferation and angiogenic ability, and increased expression of senescence-associated β-galactosidase activity. Additionally, H2O2 treatment reduced eNOS expression, enhanced p21 expression, and dephosphorylated (activated) retinoblastoma (Rb) protein. All of these alternations were attenuated by overexpression of Sirt6, while partial knockdown of Sirt6 expression by siRNA mimicked the effect of H2O2. In conclusion, these results suggest that Sirt6 is a critical regulator of endothelial senescence and oxidative stress-induced downregulation of Sirt6 is likely involved in the pathogenesis of diabetic retinopathy.
authors.affiliation: Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China ; Department of Ophthalmology and Visual Sciences, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Liu
authors.affiliation: Center for Biomedical Engineering, The University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Hua
authors.identifier: 0000-0003-2798-3337
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Ophthalmology and Visual Sciences, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA.
authors.forename: Yonju
authors.identifier: 0000-0001-9622-8410
authors.initials: Y
authors.lastname: Ha
authors.affiliation: Department of Ophthalmology and Visual Sciences, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA ; Internal Medicine, Division of Endocrinology and Stark Diabetes Center, The University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Tilton
authors.affiliation: Department of Ophthalmology and Visual Sciences, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA ; Center for Biomedical Engineering, The University of Texas Medical Branch, Galveston, TX, USA ; Neuroscience and Cell Biology, The University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Wenbo
authors.identifier: 0000-0002-8694-2554
authors.initials: W
authors.lastname: Zhang
mesh_terms: D016922:Cellular Senescence / Q000187:drug effects* / Q000235:genetics; D003930:Diabetic Retinopathy / Q000235:genetics* / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000008:administration & dosage; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis; D018384:Oxidative Stress / Q000235:genetics*; D034741:RNA, Small Interfering; D037761:Sirtuins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D034741:RNA, Small Interfering; D006861:Hydrogen Peroxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C516592:SIRT6 protein, human; D037761:Sirtuins