Oncotarget

Research Papers:

SIRT1 inhibition promotes atherosclerosis through impaired autophagy

Xiaofeng Yang, Jingyuan Wei, Yanhao He, Ting Jing, Yanxiang Li, Yunfang Xiao, Bo Wang, Weirong Wang, Jiye Zhang and Rong Lin _

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Oncotarget. 2017; 8:51447-51461. https://doi.org/10.18632/oncotarget.17691

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Abstract

Xiaofeng Yang1, Jingyuan Wei2, Yanhao He1, Ting Jing1, Yanxiang Li3, Yunfang Xiao1, Bo Wang1, Weirong Wang4, Jiye Zhang5 and Rong Lin1

1Department of Pharmacology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an 710061, Shaanxi, P. R. China

2Liaoning Province Academy of Analytic Science, Shenyang 110015, Liaoning, P. R. China

3Taizhou Polytechnic College, Taizhou 225300, Jiangsu, P. R. China

4Laboratory Animal Center, Xi’an Jiaotong University, Xi’an 710061, Shaanxi, P. R. China

5School of Pharmacology, Xi’an Jiaotong University, Xi’an 710061, Shaanxi, P. R. China

Correspondence to:

Rong Lin, email: linrong63@aliyun.com

Keywords: atherosclerosis, SIRT1, deacetylation, autophagy, Atg5

Received: October 13, 2016    Accepted: April 24, 2017    Published: May 08, 2017

ABSTRACT

SIRT1, a highly conserved NAD+-dependent protein deacetylase, plays a pivotal role in the pathogenesis and therapy of atherosclerosis (AS). The aim of this study is to investigate the potential effects of SIRT1 on AS in ApoE–/– mice and the underlying mechanisms of autophagy in an ox-LDL-stimulated human monocyte cell line, THP-1. In vivo, the accelerated atherosclerotic progression of mice was established by carotid collar placement; then, mice were treated for 4 weeks with a SIRT1-specific inhibitor, EX-527. The atherosclerotic lesion size of EX-527-treated mice was greatly increased compared to that of the mice in the control group. Immunostaining protocols confirmed that the inhibition of SIRT1 during plaque initiation and progression enhanced the extent of intraplaque macrophage infiltration and impaired the autophagy process. In vitro cultured THP-1 macrophages exposed to ox-LDL were utilized to study the link between the SIRT1 function, autophagy flux, pro-inflammatory cytokine secretion, and foam cell formation using different methods. Our data showed that ox-LDL markedly suppressed SIRT1 protein expression and the autophagy level, while it elevated the MCP-1 production and lipid uptake. Additionally, the application of the SIRT1 inhibitor EX-527 or SIRT1 siRNA further attenuated ox-LDL-induced autophagy inhibition. In conclusion, our results show that the inhibition of SIRT1 promoted atherosclerotic plaque development in ApoE–/– mice by increasing the MCP-1 expression and macrophage accumulation. In particular, we demonstrate that blocking SIRT1 can exacerbate the acetylation of key autophagy machinery, the Atg5 protein, which further regulates the THP-1 macrophage-derived foam cell formation that is triggered by ox-LDL.


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