Endothelium-specific SIRT1 overexpression inhibits hyperglycemia-induced upregulation of vascular cell senescence  被引量:16

Endothelium-specific SIRT1 overexpression inhibits hyperglycemia-induced upregulation of vascular cell senescence

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作  者:CHEN HouZao WAN YanZhen ZHOU Shuang LU YunBiao ZHANG ZhuQin ZHANG Ran CHEN Feng HAO DeLong ZHAO Xiang GUO ZhiChen LIU DePei LIANG ChihChuan 

机构地区:[1]National Laboratory of Medical Molecular Biology,Institute of Basic Medical Sciences,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100005,China [2]Department of Rheumatology and Immunology,Peking Union Medical College Hospital,Beijing 100005,China

出  处:《Science China(Life Sciences)》2012年第6期467-473,共7页中国科学(生命科学英文版)

基  金:supported by the National Basic Research Program of China (Grant No. 2011CB503902);National Natural Science Foundation of China (Grant Nos. 31028005 and 31021091)

摘  要: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 SIRTI in prevention of hyperglyce- mia-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 hyper- glycemia induced significant vascular cell senescence in aortas of mice, as indicated by upregulation of expression of senes- cence-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-I compared with diabetic WT mice. Moreover, man- ganese 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 de- creased in aortas of SIRT1-Tg diabetic mice compared with WT diabetic mice. Overall, these findings suggest that SIRT 1-mediated inhibition of hyperglycemia-induced vascular cell senescence is mediated at least partly through the reduction of oxidative stress.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.

关 键 词:SIRT1 HYPERGLYCEMIA vascular cell senescence 

分 类 号:Q516[生物学—生物化学] Q255

 

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