Original Article

Simvastatin suppresses vascular inflammation and atherosclerosis in ApoE−/− mice by downregulating the HMGB1-RAGE axis

Ming Liu, Ying Yu, Hong Jiang, Lei Zhang, Pei-pei Zhang, Peng Yu, Jian-guo Jia, Rui-zhen Chen, Yun-zeng Zou, Jun-bo Ge
DOI: 10.1038/aps.2013.8


Ming LIU1, #, Ying YU1, #, Hong JIANG1, *, Lei ZHANG1, Pei-pei ZHANG1, Peng YU1, Jian-guo JIA1, Rui-zhen CHEN2, Yun-zeng ZOU1, Jun-bo GE1
1Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai 200032, China; 2Ministry of Public Health Key Laboratory of Heart Diseases, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai 200032, China

Aim: High mobility group box protein 1 (HMGB1) and receptor for the advanced glycation end product (RAGE) play pivotal roles in vascular inflammation and atherosclerosis. The aim of this study was to determine whether the HMGB1-RAGE axis was involved in the actions of simvastatin on vascular inflammation and atherosclerosis in ApoE–/– mice.
Methods: Five-week old ApoE–/– mice and wild-type C57BL/6 mice were fed a Western diet. At 8 weeks of age, ApoE–/– mice were administered simvastatin (50 mg·kg-1·d-1) or vehicle by gavage, and the wild-type mice were treated with vehicle. The mice were sacrificed at 11 weeks of age, and the atherosclerotic lesions in aortic sinus were assessed with Oil Red O staining. Macrophage migration was determined with scanning EM and immunohistochemistry. Human umbilical vein endothelial cells (HUVECs) were used for in vitro study. Western blots were used to quantify the protein expression of HMGB1, RAGE, vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1).

Results: Vehicle-treated ApoE–/– mice exhibited significant increases in aortic inflammation and atherosclerosis as well as enhanced expression of HMGB1, RAGE, VCAM-1, and MCP-1 in aortic tissues as compared to the wild-type mice. Furthermore, serum total cholesterol, triglyceride and LDL levels were markedly increased, while serum HDL level was decreased in vehicle-treated ApoE–/– mice. Administration with simvastatin in ApoE–/– mice markedly attenuated the vascular inflammation and atherosclerotic lesion area, and decreased the aortic expression of HMGB1, RAGE, VCAM-1, and MCP-1. However, simvastatin did not affect the abnormal levels of serum total cholesterol, triglyceride, LDL and HDL in ApoE–/– mice. Exposure of HUVECs to HMGB1 (100 ng/mL) markedly increased the expression of HMGB1, RAGE and VCAM-1, whereas pretreatment of the cells with simvastatin (10 μmol/L) blocked the HMGB1-caused changes.

Conclusion: Simvastatin inhibits vascular inflammation and atherosclerosis in ApoE–/– mice, which may be mediated through down­regulation of the HMGB1-RAGE axis.

Keywords: atherosclerosis; inflammation; simvastatin; ApoE–/– mice; human umbilical vein endothelial cells (HUVECs); aortic sinus; HMGB1; RAGE; VCAM-1; MCP-1; macrophages

This study was supported by grants from the National Natural Science Foundation of China (No 81170221) and the Janssen Research Council China.

# These authors contributed equally to this work.
* To whom correspondence should be addressed.
E-mail jiang.hong@zs-hospital.sh.cn
Received 2012-10-30 Accepted 2013-01-19

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