Metformin modulates hyperglycaemia-induced endothelial senescence and apoptosis through SIRT1.
Metformin modulates hyperglycaemia-induced endothelial senescence and apoptosis through SIRT1.
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DOI：
10.1111/bph.12496
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发表时间：
2014-01
影响因子：
7.3
通讯作者：
Triggle CR
中科院分区：
文献类型：
--
作者：
Arunachalam G;Samuel SM;Marei I;Ding H;Triggle CR
背景和目的：内皮功能障碍可在糖尿病相关微血管疾病发展的早期检测到，并与加速内皮衰老和老化有关。 高血压诱导的氧化应激是内皮功能障碍发展的主要因素。临床数据表明，降血糖药物二甲双胍具有内皮保护作用;然而，其分子和细胞机制仍不清楚。在本研究中，我们研究了二甲双胍在高血压诱导的小鼠微血管内皮细胞（MMECs）衰老过程中的保护作用。实验方法：在存在和不存在二甲双胍（50 μM）的情况下，在正常葡萄糖（11 mM）和高葡萄糖（HG; 40 mM）中培养MMEC 72 h。 通过免疫印迹和免疫细胞技术测定sirtuin-1（SIRT 1）和衰老/衰老相关标志物的表达。用适当的siRNA抑制SIRT 1表达。关键结果：暴露于HG的MMECs显著降低SIRT 1蛋白表达，增加叉头框O 1（FoxO-1）和p53乙酰化，增加p21和降低Bcl 2表达。 此外，HG中MMECs中衰老相关的β-半乳糖苷酶活性增加。二甲双胍治疗减弱了HG诱导的SIRT 1表达减少，调节SIRT 1下游靶点FoxO-1和p53/p21，并保护内皮细胞免受HG诱导的早衰。然而，在SIRT 1基因敲除后，二甲双胍的作用丧失。结论和意义：HG诱导的SIRT 1下调在糖尿病诱导的内皮细胞衰老中起着至关重要的作用。 此外，二甲双胍对HG诱导的内皮功能障碍的保护作用部分是由于其对SIRT 1表达和/或活性的影响。
Background and Purpose: Endothelial dysfunction can be detected at an early stage in the development of diabetes-related microvascular disease and is associated with accelerated endothelial senescence and ageing. Hyperglycaemia-induced oxidative stress is a major contributing factor to the development of endothelial dysfunction. Clinical data indicate that the hypoglycaemic agent, metformin, has an endothelial protective action; however, its molecular and cellular mechanisms remain elusive. In the present study, we have investigated the protective effect of metformin during hyperglycaemia-induced senescence in mouse microvascular endothelial cells (MMECs). Experimental Approach: MMECs were cultured in normal glucose (11 mM) and high glucose (HG; 40 mM) in the presence and absence of metformin (50 μM) for 72 h. The expression of sirtuin-1 (SIRT1) and senescence/apoptosis-associated markers was determined by immunoblotting and immunocyto techniques. SIRT1 expression was inhibited with appropriate siRNA. Key Results: Exposure of MMECs to HG significantly reduced SIRT1 protein expression, increased forkhead box O1 (FoxO-1) and p53 acetylation, increased p21 and decreased Bcl2 expression. In addition, senescence-associated β-galactosidase activity in MMECs was increased in HG. Treatment with metformin attenuated the HG-induced reduction of SIRT1 expression, modulated the SIRT1 downstream targets FoxO-1 and p53/p21, and protected endothelial cells from HG-induced premature senescence. However, following gene knockdown of SIRT1 the effects of metformin were lost. Conclusions and Implications: HG-induced down-regulation of SIRT1 played a crucial role in diabetes-induced endothelial senescence. Furthermore, the protective effect of metformin against HG-induced endothelial dysfunction was partly due to its effects on SIRT1 expression and/or activity.
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影响因子：
7.7
作者：
Detaille, D;Guigas, B;Leverve, X
通讯作者：
Leverve, X
DOI：
10.1152/ajpheart.00486.2008
发表时间：
2008-09-01
影响因子：
4.8
作者：
Matsumoto, Takayuki;Noguchi, Eri;Kamata, Katsuo
通讯作者：
Kamata, Katsuo
影响因子：
2.1
作者：
Hou J;Chong ZZ;Shang YC;Maiese K
通讯作者：
Maiese K
DOI：
10.1016/j.bbrc.2010.01.080
发表时间：
2010-02-26
影响因子：
3.1
作者：
Arunachalam, Gnanapragasam;Yao, Hongwei;Sundar, Isaac K.;Caito, Samuel;Rahman, Irfan
通讯作者：
Rahman, Irfan
影响因子：
56.9
作者：
Brunet, A;Sweeney, LB;Greenberg, ME
通讯作者：
Greenberg, ME