Dataset Information

SIRT1-mediated ER? suppression in the endothelium contributes to vascular aging.

ABSTRACT: 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 ER? expression in the endothelium was reduced in aging mice, and the expression of ER? and SIRT1 did not change, while SIRT1 activity declined. Further investigation showed that the ER? expression was regulated by SIRT1 through complexes of SIRT1-PPAR?/RXR-p300 that bind to a PPRE (PPAR response element) site on the ER? 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 ER? 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 ER? 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 ER? suppression in the endothelium contributes to vascular aging, and the modulation of SIRT1 phosphorylation through a single-mutant SIRT1-C152(D) restores this effect.

SUBMITTER: Kong D

PROVIDER: S-EPMC6398526 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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SIRT1-mediated ERβ suppression in the endothelium contributes to vascular aging.

Kong Danli D Zhan Ying Y Liu Zhaoyu Z Ding Ting T Li Min M Yu Haibing H Zhang Laxi L Li Huawen H Luo Aiyue A Zhang Dongwei D Wang Yifei Y Wang Shixuan S Zhang Zhefan Z Zhang Hongyu H Huang Xiaodong X Yao Paul P Ding Yuanling Y Liu Zhengxiang Z

Aging cell 20160729 6

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 ...[more]

PMID: 27470296

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Project description:ObjectiveAngiotensin II (AngII) has been shown to regulate angiogenesis and at high pathophysiological doses to cause vasoconstriction through the AngII receptor type 1. Angiotensin 1 to 7 (Ang-(1-7)) acting through the Mas1 receptor can act antagonistically to high pathophysiological levels of AngII by inducing vasodilation, whereas the effects of Ang-(1-7) signaling on angiogenesis are less defined. To complicate the matter, there is growing evidence that a subpressor dose of AngII produces phenotypes similar to Ang-(1-7).Approach and resultsThis study shows that low-dose Ang-(1-7), acting through the Mas1 receptor, promotes angiogenesis and vasodilation similar to a low, subpressor dose of AngII acting through AngII receptor type 1. In addition, we show through in vitro tube formation that Ang-(1-7) augments the angiogenic response in rat microvascular endothelial cells. Using proteomic and genomic analyses, downstream components of Mas1 receptor signaling were identified, including Rho family of GTPases, phosphatidylinositol 3-kinase, protein kinase D1, mitogen-activated protein kinase, and extracellular signal-related kinase signaling. Further experimental antagonism of extracellular signal-related kinases 1/2 and p38 mitogen-activated protein kinase signaling inhibited endothelial tube formation and vasodilation when stimulated with equimolar, low doses of either AngII or Ang-(1-7).ConclusionsThese results significantly expand the known Ang-(1-7)/Mas1 receptor signaling pathway and demonstrate an important distinction between the pathological effects of elevated and suppressed AngII compared with the beneficial effects of AngII normalization and Ang-(1-7) administration. The observed convergence of Ang-(1-7)/Mas1 and AngII/AngII receptor type 1 signaling at low ligand concentrations suggests a nuanced regulation in vasculature. These data also reinforce the importance of mitogen-activated protein kinase/extracellular signal-related kinase signaling in maintaining vascular function.

Dataset Information

SIRT1-mediated ER? suppression in the endothelium contributes to vascular aging.

Publications

SIRT1-mediated ERβ suppression in the endothelium contributes to vascular aging.

Similar Datasets

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