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.
Highlights
Atherosclerosis (AS), a long-term inflammatory disease characterized by atheromatous plaques in the intima of the large arteries, is an underlying cause of many cardiovascular diseases, including heart attack and stroke [1, 2]
There was no significant difference in the body weight of the control groups or in the EX-527-treated groups compared with the sham group (P > 0.05, data not shown)
The H&E staining of the left common carotid sections showed that the collar-induced mice (8 wks) exhibited noticeable plaque areas, which were accompanied by increased foam cell formation compared to sham-operated mice (0 wk), as evidenced by Oil Red O (ORO) staining of the sections
Summary
Atherosclerosis (AS), a long-term inflammatory disease characterized by atheromatous plaques in the intima of the large arteries, is an underlying cause of many cardiovascular diseases, including heart attack and stroke [1, 2]. This progressive and insidious disease is the leading cause of death and morbidity among adults worldwide [3]. Despite the increasing evidence of in macrophage autophagy in AS, its accurate mechanisms remain to be thoroughly investigated
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have