Research Papers:
SIRT1 inhibition promotes atherosclerosis through impaired autophagy
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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: [email protected]
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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PII: 17691