PMID- 23564080
OWN - NLM
STAT- MEDLINE
DCOM- 20140106
LR  - 20211021
IS  - 1745-7254 (Electronic)
IS  - 1671-4083 (Print)
IS  - 1671-4083 (Linking)
VI  - 34
IP  - 6
DP  - 2013 Jun
TI  - Simvastatin suppresses vascular inflammation and atherosclerosis in ApoE(-/-) 
      mice by downregulating the HMGB1-RAGE axis.
PG  - 830-6
LID - 10.1038/aps.2013.8 [doi]
AB  - 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 mumol/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.
FAU - Liu, Ming
AU  - Liu M
AD  - Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai 
      Medical College, Fudan University, Shanghai 200032, China.
FAU - Yu, Ying
AU  - Yu Y
FAU - Jiang, Hong
AU  - Jiang H
FAU - Zhang, Lei
AU  - Zhang L
FAU - Zhang, Pei-pei
AU  - Zhang PP
FAU - Yu, Peng
AU  - Yu P
FAU - Jia, Jian-guo
AU  - Jia JG
FAU - Chen, Rui-zhen
AU  - Chen RZ
FAU - Zou, Yun-zeng
AU  - Zou YZ
FAU - Ge, Jun-bo
AU  - Ge JB
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130408
PL  - United States
TA  - Acta Pharmacol Sin
JT  - Acta pharmacologica Sinica
JID - 100956087
RN  - 0 (Apolipoproteins E)
RN  - 0 (HMGB1 Protein)
RN  - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors)
RN  - 0 (Receptor for Advanced Glycation End Products)
RN  - 0 (Receptors, Immunologic)
RN  - AGG2FN16EV (Simvastatin)
SB  - IM
MH  - Animals
MH  - Aorta/drug effects/pathology
MH  - Apolipoproteins E/genetics
MH  - Atherosclerosis/*drug therapy/pathology
MH  - Blotting, Western
MH  - Down-Regulation/drug effects
MH  - HMGB1 Protein/genetics
MH  - Human Umbilical Vein Endothelial Cells
MH  - Humans
MH  - Hydroxymethylglutaryl-CoA Reductase Inhibitors/*pharmacology
MH  - Inflammation/*drug therapy/pathology
MH  - Macrophages/drug effects/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Receptor for Advanced Glycation End Products
MH  - Receptors, Immunologic/genetics
MH  - Simvastatin/*pharmacology
PMC - PMC4002903
EDAT- 2013/04/09 06:00
MHDA- 2014/01/07 06:00
PMCR- 2013/06/01
CRDT- 2013/04/09 06:00
PHST- 2013/04/09 06:00 [entrez]
PHST- 2013/04/09 06:00 [pubmed]
PHST- 2014/01/07 06:00 [medline]
PHST- 2013/06/01 00:00 [pmc-release]
AID - aps20138 [pii]
AID - 10.1038/aps.2013.8 [doi]
PST - ppublish
SO  - Acta Pharmacol Sin. 2013 Jun;34(6):830-6. doi: 10.1038/aps.2013.8. Epub 2013 Apr 
      8.