Abstract
The rapidly increasing prevalence of diabetes mellitus worldwide is one of the most serious and challenging health problems in the 21st century. Mammalian sirtuin 1 (SIRT1) has been shown to decrease high-glucose-induced endothelial cell senescence in vitro and prevent hyperglycemia-induced vascular dysfunction. However, a role for SIRT1 in prevention of hyperglycemia-induced vascular cell senescence in vivo remains unclear. We used endothelium-specific SIRT1 transgenic (SIRT1-Tg) mice and wild-type (WT) mice to construct a 40-week streptozotocin (STZ)-induced diabetic mouse model. In this mode, 42.9% of wild-type (WT) mice and 38.5% of SIRT1-Tg mice were successfully established as diabetic. Forty weeks of hyperglycemia induced significant vascular cell senescence in aortas of mice, as indicated by upregulation of expression of senescence-associated markers including p53, p21 and plasminogen activator inhibitor-1 (PAI-1). However, SIRT1-Tg diabetic mice displayed dramatically decreased expression of p53, p21 and PAI-1 compared with diabetic WT mice. Moreover, manganese superoxide dismutase expression (MnSOD) was significantly downregulated in the aortas of diabetic WT mice, but was preserved in diabetic SIRT1-Tg mice. Furthermore, expression of the oxidative stress adaptor p66Shc was significantly decreased in aortas of SIRT1-Tg diabetic mice compared with WT diabetic mice. Overall, these findings suggest that SIRT1-mediated inhibition of hyperglycemia-induced vascular cell senescence is mediated at least partly through the reduction of oxidative stress.
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Wild S, Roglic G, Green A, et al. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care, 2004, 27: 1047–1053
Fox C S, Coady S, Sorlie P D, et al. Trends in cardiovascular complications of diabetes. JAMA, 2004, 292: 2495–2499
Libby P, Ridker P M, Hansson G K. Progress and challenges in translating the biology of atherosclerosis. Nature, 2011, 473: 317–325
de Haan J B, Cooper M E. Targeted antioxidant therapies in hyperglycemia-mediated endothelial dysfunction. Front Biosci (Schol Ed), 2011, 3: 709–729
Sitia S, Tomasoni L, Atzeni F, et al. From endothelial dysfunction to atherosclerosis. Autoimmun Rev, 2010, 9: 830–834
Minamino T, Miyauchi H, Yoshida T, et al. Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction. Circulation, 2002, 105: 1541–1544
Vasile E, Tomita Y, Brown L F, et al. Differential expression of thymosin beta-10 by early passage and senescent vascular endothelium is modulated by VPF/VEGF: evidence for senescent endothelial cells in vivo at sites of atherosclerosis. FASEB J, 2001, 15: 458–466
Brodsky S V, Gealekman O, Chen J, et al. Prevention and reversal of premature endothelial cell senescence and vasculopathy in obesity-induced diabetes by ebselen. Circ Res, 2004, 94: 377–384
Matsui-Hirai H, Hayashi T, Yamamoto S, et al. Dose-dependent modulatory effects of insulin on glucose-induced endothelial senescence in vitro and in vivo: a relationship between telomeres and nitric oxide. J Pharmacol Exp Ther, 2011, 337: 591–599
Chen J, Brodsky S V, Goligorsky D M, et al. Glycated collagen I induces premature senescence-like phenotypic changes in endothelial cells. Circ Res, 2002, 90: 1290–1298
Guarani V, Potente M. SIRT1—a metabolic sensor that controls blood vessel growth. Curr Opin Pharmacol, 2010, 10: 139–145
Longo V D, Kennedy B K. Sirtuins in aging and age-related disease. Cell, 2006, 126: 257–268
Zhang Q J, Wang Z, Chen H Z, et al. Endothelium-specific overexpression of class III deacetylase SIRT1 decreases atherosclerosis in apolipoprotein E-deficient mice. Cardiovasc Res, 2008, 80: 191–199
Zhou S, Chen H Z, Wan Y Z, et al. Repression of P66Shc expression by SIRT1 contributes to the prevention of hyperglycemia-induced endothelial dysfunction. Circ Res, 2011, 109: 639–648
Itahana K, Dimri G, Campisi J. Regulation of cellular senescence by p53. Eur J Biochem, 2001, 268: 2784–2791
Lundberg A S, Hahn W C, Gupta P, et al. Genes involved in senescence and immortalization. Curr Opin Cell Biol, 2000, 12: 705–709
Kortlever R M, Higgins P J, Bernards R. Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence. Nat Cell Biol, 2006, 8: 877–884
Tanaka T, Yokote K. Epigenetic regulation and molecular mechanisms of cellular senescence by tumor suppressor p53. Nihon Ronen Igakkai Zasshi, 2011, 48: 134–137
Erusalimsky J D. Vascular endothelial senescence: from mechanisms to pathophysiology. J Appl Physiol, 2009, 106: 326–332
Nishikawa T, Edelstein D, Du X L, et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature, 2000, 404: 787–790
Migliaccio E, Giorgio M, Mele S, et al. The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature, 1999, 402: 309–313
Giorgio M, Migliaccio E, Orsini F, et al. Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis. Cell, 2005, 122: 221–233
Miyauchi H, Minamino T, Tateno K, et al. Akt negatively regulates the in vitro lifespan of human endothelial cells via a p53/p21-dependent pathway. EMBO J, 2004, 23: 212–220
Zhong W, Zou G, Gu J, et al. L-arginine attenuates high glucose-accelerated senescence in human umbilical vein endothelial cells. Diabetes Res Clin Pract, 2010, 89: 38–45
Ota H, Eto M, Kano M R, et al. Induction of endothelial nitric oxide synthase, SIRT1, and catalase by statins inhibits endothelial senescence through the Akt pathway. Arterioscler Thromb Vasc Biol, 2010, 30: 2205–2211
Borradaile N M, Pickering J G. Nicotinamide phosphoribosy-ltransferase imparts human endothelial cells with extended replicative lifespan and enhanced angiogenic capacity in a high glucose environment. Aging Cell, 2009, 8: 100–112
Orimo M, Minamino T, Miyauchi H, et al. Protective role of SIRT1 in diabetic vascular dysfunction. Arterioscler Thromb Vasc Biol, 2009, 29: 889–894
Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature, 2001, 414: 813–820
Zhang R, Chen H Z, Liu J J, et al. SIRT1 suppresses activator protein-1 transcriptional activity and cyclooxygenase-2 expression in macrophages. J Biol Chem, 2010, 285: 7097–7110
Erusalimsky J D, Kurz D J. Endothelial cell senescence. Handb Exp Pharmacol, 2006, 176: 213–248
Lee R Y, Hench J, Ruvkun G. Regulation of C. elegans DAF-16 and its human ortholog FKHRL1 by the daf-2 insulin-like signaling pathway. Curr Biol, 2001, 11: 1950–1957
Kenyon C. A conserved regulatory system for aging. Cell, 2001, 105: 165–168
Lin K, Hsin H, Libina N, et al. Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling. Nat Genet, 2001, 28: 139–145
Bluher M, Kahn B B, Kahn C R. Extended longevity in mice lacking the insulin receptor in adipose tissue. Science, 2003, 299: 572–574
Holzenberger M, Dupont J, Ducos B, et al. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature, 2003, 421: 182–187
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Chen, H., Wan, Y., Zhou, S. et al. Endothelium-specific SIRT1 overexpression inhibits hyperglycemia-induced upregulation of vascular cell senescence. Sci. China Life Sci. 55, 467–473 (2012). https://doi.org/10.1007/s11427-012-4329-4
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DOI: https://doi.org/10.1007/s11427-012-4329-4