内皮
生物
内分泌学
内科学
磷酸化
受体
雌激素受体
细胞生物学
西妥因1
生物化学
下调和上调
基因
医学
遗传学
癌症
乳腺癌
作者
Danli Kong,Ying Zhan,Zhaoyu Liu,Ting Ding,Min Li,Haibing Yu,Laxi Zhang,Huawen Li,Aiyue Luo,Dongwei Zhang,Yifei Wang,Shixuan Wang,Zhefan Zhang,Hongyu Zhang,Xiaodong Huang,Paul Yao,Yuanling Ding,Zhengxiang Liu
出处
期刊:Aging Cell
[Wiley]
日期:2016-07-29
卷期号:15 (6): 1092-1102
被引量:40
摘要
SIRT1 has many important molecular functions in aging, and the estrogen receptors (ERs) have a vasculoprotective effect, although the detailed mechanism for the roles of SIRT1 and ERs in vascular aging remains unclear. We found that ERβ expression in the endothelium was reduced in aging mice, and the expression of ERα and SIRT1 did not change, while SIRT1 activity declined. Further investigation showed that the ERβ expression was regulated by SIRT1 through complexes of SIRT1-PPARγ/RXR-p300 that bind to a PPRE (PPAR response element) site on the ERβ promoter, and the declined SIRT1 function in aging mice was due to compromised phosphorylation at S154. A single-mutant SIRT1-C152(D) restored the reduced ERβ expression in the endothelium with minimized reactive oxygen species generation and DNA damage and increased mitochondrial function and fatty acid metabolism. In high-fat diet aging mice, the endothelium-specific delivery of ERβ or SIRT1-C152(D) on the vascular wall reduced the circulating lipids with ameliorated vascular damage, including the restored vessel tension and blood pressure. We conclude that SIRT1-mediated ERβ suppression in the endothelium contributes to vascular aging, and the modulation of SIRT1 phosphorylation through a single-mutant SIRT1-C152(D) restores this effect.
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