Oncotarget

Research Papers: Gerotarget (Focus on Aging):

Endothelial SIRT1 prevents adverse arterial remodeling by facilitating HERC2-mediated degradation of acetylated LKB1

Bo Bai, Andy W.C. Man, Kangmin Yang, Yumeng Guo, Cheng Xu, Hung-Fat Tse, Weiping Han, Maria Bloksgaard, Jo G.R. De Mey, Paul M. Vanhoutte, Aimin Xu and Yu Wang _

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Oncotarget. 2016; 7:39065-39081. https://doi.org/10.18632/oncotarget.9687

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Abstract

Bo Bai1,3,*, Andy W.C. Man1,*, Kangmin Yang1, Yumeng Guo1, Cheng Xu1, Hung-Fat Tse2, Weiping Han3, Maria Bloksgaard4, Jo G.R. De Mey4, Paul M. Vanhoutte1, Aimin Xu1,2 and Yu Wang1

1 State Key Laboratory of Pharmaceutical Biotechnology and Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China

2 Department of Medicine, The University of Hong Kong, Hong Kong, China

3 Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR), Singapore

4 Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark

* Co-first authors

Correspondence to:

Yu Wang, email:

Keywords: hypertension, blood vessel remodeling, endothelial senescence, SIRT1, LKB1, Gerotarget

Received: February 29, 2016 Accepted: May 23, 2016 Published: May 29, 2016

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 TGFβ1 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 TGFβ1 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 fine-tunes the crosstalk between endothelial and vascular smooth muscle cells to prevent adverse arterial remodeling and maintain vascular homeostasis.


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