High glucose induced alteration of SIRTs in endothelial cells causes rapid aging in a p300 and FOXO regulated pathway.
High glucose induced alteration of SIRTs in endothelial cells causes rapid aging in a p300 and FOXO regulated pathway.
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DOI：
10.1371/journal.pone.0054514
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Chakrabarti S
中科院分区：
文献类型：
--
作者：
Mortuza R;Chen S;Feng B;Sen S;Chakrabarti S
在糖尿病中，一些细胞变化与衰老相似。我们假设高血糖加速内皮细胞（EC）和组织的衰老样变化，导致结构和功能损伤。我们用衰老相关β-gal（SA β-gal）染色和细胞形态学方法研究了葡萄糖诱导的3种内皮细胞衰老。研究了sirtuins（SIRTs）及其下游介质FOXO和氧化应激的变化。研究了这种改变与组蛋白乙酰化酶（HAT）p300的关系。在糖尿病动物的组织中进行类似的检查。高糖环境下内皮细胞SA β-gal阳性率增加，复制能力下降，可见内皮细胞早期衰老。这些变化在微血管内皮细胞中明显。它们形成了不规则和肥大的表型。这种变化与SIRT（1-7）mRNA表达降低有关。我们还发现p300和SIRT 1在这个过程中相互调节，因为沉默一个导致其他人的表达增加。此外，HG导致FOXO 1的DNA结合能力和抗氧化靶基因表达降低。化学诱导的SIRT 1活性增加和p300敲低纠正了这些异常，减缓了衰老样变化。糖尿病动物表现出肾小球和视网膜血管沿着细胞衰老增加，这些组织中SIRT 1 mRNA表达减少。这项研究的数据表明，高血糖加速血管EC中的衰老样过程，并且该过程通过SIRT 1的下调介导，导致p300和FOXO 1介导的途径中的线粒体抗氧化酶减少。
In diabetes, some of the cellular changes are similar to aging. We hypothesized that hyperglycemia accelerates aging-like changes in the endothelial cells (ECs) and tissues leading to structural and functional damage. We investigated glucose-induced aging in 3 types of ECs using senescence associated β-gal (SA β-gal) staining and cell morphology. Alterations of sirtuins (SIRTs) and their downstream mediator FOXO and oxidative stress were investigated. Relationship of such alteration with histone acetylase (HAT) p300 was examined. Similar examinations were performed in tissues of diabetic animals. ECs in high glucose (HG) showed evidence of early senescence as demonstrated by increased SA β-gal positivity and reduced replicative capacities. These alterations were pronounced in microvascular ECs. They developed an irregular and hypertrophic phenotype. Such changes were associated with decreased SIRT (1–7) mRNA expressions. We also found that p300 and SIRT1 regulate each other in such process, as silencing one led to increase of the others’ expression. Furthermore, HG caused reduction in FOXO1’s DNA binding ability and antioxidant target gene expressions. Chemically induced increased SIRT1 activity and p300 knockdown corrected these abnormalities slowing aging-like changes. Diabetic animals showed increased cellular senescence in renal glomerulus and retinal blood vessels along with reduced SIRT1 mRNA expressions in these tissues. Data from this study demonstrated that hyperglycemia accelerates aging-like process in the vascular ECs and such process is mediated via downregulation of SIRT1, causing reduction of mitochondrial antioxidant enzyme in a p300 and FOXO1 mediated pathway.
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影响因子：
9.8
作者：
Bordone L;Motta MC;Picard F;Robinson A;Jhala US;Apfeld J;McDonagh T;Lemieux M;McBurney M;Szilvasi A;Easlon EJ;Lin SJ;Guarente L
通讯作者：
Guarente L
DOI：
10.18632/aging.100062
发表时间：
2009-06-29
期刊：
Aging
影响因子：
--
作者：
Nakagawa T;Guarente L
通讯作者：
Guarente L
DOI：
10.1073/pnas.1434429100
发表时间：
2003-09-16
影响因子：
11.1
作者：
Chi, JT;Chang, HY;Brown, PO
通讯作者：
Brown, PO
影响因子：
7.7
作者：
Feng B;Chen S;McArthur K;Wu Y;Sen S;Ding Q;Feldman RD;Chakrabarti S
通讯作者：
Chakrabarti S
影响因子：
--
作者：
Mozaffarian, Dariush;Kamineni, Aruna;Carnethon, Mercedes;Djousse, Luc;Mukamal, Kenneth J.;Siscovick, David
通讯作者：
Siscovick, David