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:ObjectiveDysregulated adipokine profiles contribute to the pathogenesis of diabetic cardiovascular complications. Endothelial cell (EC) dysfunction, a common pathological alteration in cardiovascular disorders, is exaggerated in diabetes. However, it is unclear whether and how dysregulated adipokines may contribute to diabetic EC dysfunction.Methods and resultsSerum C1q/TNF-Related Protein 5 (CTRP5) were determined in control/diabetes patients, and control/diabetic mice (high-fat diet, HFD). We observed for the first time that serum total CTRP5 was increased, high molecular weight (HMW) form was decreased, but the globular form (gCTRP5) was significantly increased in diabetic patients. These pathological alterations were reproduced in diabetic mice. To determine the pathological significance of increased gCTRP5 in diabetes, in vivo, ex vivo and in vitro experiments were performed. Diabetic atherosclerosis and EC dysfunction were significantly attenuated by the in vivo administration of CTRP5 neutralization antibody (CTRP5Ab). EC apoptosis was significantly increased in diabetic EC (isolated from HFD animal aorta) or high glucose high lipid (HGHL) cultured HUVECs. These pathological alterations were further potentiated by gCTRP5 and attenuated by CTRP5Ab. Pathway specific discovery-driven approach revealed that Nox1 expression was one of the signaling molecules commonly activated by HFD, HGHL, and gCTRP5. Treatment with CTRP5Ab reversed HFD-induced Nox1 upregulation. Finally, Nox1siRNA was used to determine the causative role of Nox1 in gCTRP5 induced EC apoptosis in diabetes. Results showed that gCTRP5 activated the mitochondrial apoptotic signal of EC in diabetes, which was blocked by the silencing Nox1 gene.ConclusionWe demonstrated for the first time that gCTRP5 is a novel molecule contributing to diabetic vascular EC dysfunction through Nox1-mediated mitochondrial apoptosis, suggesting that interventions blocking gCTRP5 may protect diabetic EC function, ultimately attenuate diabetic cardiovascular complications.

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.

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