Please use this identifier to cite or link to this item: https://doi.org/10.18632/oncotarget.9687
Title: Endothelial SIRT1 prevents adverse arterial remodeling by facilitating HERC2-mediated degradation of acetylated LKB1
Authors: Bai, B
Man, A.W.C
Kangmin Yang, State Key Laboratory of Pharmaceutical Biotechnology, Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong
Yumeng Guo, State Key Laboratory of Pharmaceutical Biotechnology, Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong
Cheng Xu, State Key Laboratory of Pharmaceutical Biotechnology, Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong
Tse, H.-F
Han, W 
Bloksgaard, M
De Mey, J.G.R
Vanhoutte, P.M
Xu, A
Wang, Y
Keywords: endothelial nitric oxide synthase
HECT and RLD domain containing E3 ubiquitin protein ligase 2
protein kinase
protein kinase LKB1
sirtuin 1
transforming growth factor beta1
unclassified drug
endothelial nitric oxide synthase
guanine nucleotide exchange factor
HERC2 protein, human
protein serine threonine kinase
SIRT1 protein, human
sirtuin 1
STK11 protein, human
ubiquitin
aging
animal cell
Article
binding affinity
binding site
bioaccumulation
cell aging
cell proliferation
chromatin immunoprecipitation
complex formation
controlled study
down regulation
gene
gene function
gene identification
HECT and RLD domain containing E3 ubiquitin protein ligase 2 gene
human
human cell
in vitro study
molecular dynamics
mouse
nonhuman
polymerase chain reaction
protein binding
protein determination
protein function
protein protein interaction
quantitative analysis
sirtuin 1 gene
site directed mutagenesis
vascular aging
vascular remodeling
vascular smooth muscle cell
3T3-L1 cell line
acetylation
animal
artery
carotid artery
chemistry
endothelium cell
genetics
homeostasis
metabolism
pathology
protein processing
transgenic mouse
tumor cell line
vascular endothelium
vascular remodeling
vascular smooth muscle
3T3-L1 Cells
Acetylation
Animals
Arteries
Carotid Arteries
Cell Line, Tumor
Endothelial Cells
Endothelium, Vascular
Guanine Nucleotide Exchange Factors
Homeostasis
Humans
Mice
Mice, Transgenic
Muscle, Smooth, Vascular
Mutagenesis, Site-Directed
Nitric Oxide Synthase Type III
Protein Processing, Post-Translational
Protein-Serine-Threonine Kinases
Sirtuin 1
Ubiquitin
Vascular Remodeling
Issue Date: 2016
Publisher: Impact Journals LLC
Citation: Bai, B, Man, A.W.C, Kangmin Yang, State Key Laboratory of Pharmaceutical Biotechnology, Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, Yumeng Guo, State Key Laboratory of Pharmaceutical Biotechnology, Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, Cheng Xu, State Key Laboratory of Pharmaceutical Biotechnology, Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, Tse, H.-F, Han, W, Bloksgaard, M, De Mey, J.G.R, Vanhoutte, P.M, Xu, A, Wang, Y (2016). Endothelial SIRT1 prevents adverse arterial remodeling by facilitating HERC2-mediated degradation of acetylated LKB1. Oncotarget 7 (26) : 39065-39081. ScholarBank@NUS Repository. https://doi.org/10.18632/oncotarget.9687
Rights: Attribution 4.0 International
Abstract: Aims-SIRT1 exerts potent activity against cellular senescence and vascular ageing. By decreasing LKB1 protein levels, it promotes the survival and regeneration of endothelial cells. The present study aims to investigate the molecular mechanisms underlying SIRT1-mediated LKB1 degradation for the prevention of vascular ageing. Methods and Results-Co-immunoprecipitation assay demonstrated that SIRT1, via its amino-terminus, binds to the DOC domain of HERC2 [HECT and RLD domain containing E3 ubiquitin protein ligase 2], which then ubiquitinates LKB1 in the nuclear compartment of endothelial cells. Site-directed mutagenesis revealed that acetylation at lysine (K) 64 of LKB1 triggers the formation of SIRT1/HERC2/LKB1 protein complex and subsequent proteasomal degradation. In vitro cellular studies suggested that accumulation of acetylated LKB1 in the nucleus leads to endothelial activation, in turn stimulating the proliferation of vascular smooth muscle cells and the production of extracellular matrix proteins. Chromatin immunoprecipitation quantitative PCR confirmed that acetylated LKB1 interacts with and activates TGF?1 promoter, which is inhibited by SIRT1. Knocking down either SIRT1 or HERC2 results in an increased association of LKB1 with the positive regulatory elements of TGF?1 promoter. In mice without endothelial nitric oxide synthase, selective overexpression of human SIRT1 in endothelium prevents hypertension and age-related adverse arterial remodeling. Lentiviral-mediated knockdown of HERC2 abolishes the beneficial effects of endothelial SIRT1 on both arterial remodeling and arterial blood pressure control. Conclusion-By downregulating acetylated LKB1 protein via HERC2, SIRT1 finetunes the crosstalk between endothelial and vascular smooth muscle cells to prevent adverse arterial remodeling and maintain vascular homeostasis.
Source Title: Oncotarget
URI: https://scholarbank.nus.edu.sg/handle/10635/180387
ISSN: 1949-2553
DOI: 10.18632/oncotarget.9687
Rights: Attribution 4.0 International
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