title: Simvastatin suppresses vascular inflammation and atherosclerosis in ApoE(-/-) mice by downregulating the HMGB1-RAGE axis.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  Simvastatin inhibits vascular inflammation and atherosclerosis in ApoE(-/-) mice, which may be mediated through downregulation of the HMGB1-RAGE axis.
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.forename: Ying
authors.initials: Y
authors.lastname: Yu
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Pei-pei
authors.initials: PP
authors.lastname: Zhang
authors.forename: Peng
authors.initials: P
authors.lastname: Yu
authors.forename: Jian-guo
authors.initials: JG
authors.lastname: Jia
authors.forename: Rui-zhen
authors.initials: RZ
authors.lastname: Chen
authors.forename: Yun-zeng
authors.initials: YZ
authors.lastname: Zou
authors.forename: Jun-bo
authors.initials: JB
authors.lastname: Ge
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy* / Q000473:pathology; D015153:Blotting, Western; D015536:Down-Regulation / Q000187:drug effects; D024243:HMGB1 Protein / Q000235:genetics; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy* / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics; D019821:Simvastatin / Q000494:pharmacology*
chemical_list: D001057:Apolipoproteins E; D024243:HMGB1 Protein; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D019821:Simvastatin
references.citation: Diabetologia. 2008 Sep;51(9):1731-40
references.pmid: 18594792
references.citation: Circ Res. 1999 Aug 20;85(4):377-85
references.pmid: 10455066
references.citation: Methods Mol Med. 2006;129:83-95
references.pmid: 17085806
references.citation: Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2010 May;22(5):306-8
references.pmid: 20519084
references.citation: Arterioscler Thromb Vasc Biol. 2011 Feb;31(2):313-9
references.pmid: 21088249
references.citation: Nat Med. 1998 Sep;4(9):1025-31
references.pmid: 9734395
references.citation: Neurosci Lett. 2010 Mar 8;471(3):152-6
references.pmid: 20100543
references.citation: Curr Opin Pharmacol. 2006 Apr;6(2):130-5
references.pmid: 16487750
references.citation: Curr Treat Options Cardiovasc Med. 2005 Dec;7(6):459-66
references.pmid: 16283973
references.citation: Circ J. 2010 May;74(5):818-26
references.pmid: 20424337
references.citation: Circulation. 2002 Nov 26;106(22):2827-35
references.pmid: 12451010
references.citation: N Engl J Med. 1999 Jan 14;340(2):115-26
references.pmid: 9887164
references.citation: Blood. 2003 Apr 1;101(7):2652-60
references.pmid: 12456506
references.citation: Arterioscler Thromb Vasc Biol. 2004 Dec;24(12):2320-5
references.pmid: 15374849
references.citation: Arterioscler Thromb Vasc Biol. 2006 Dec;26(12):2716-23
references.pmid: 17038636
references.citation: Circulation. 2003 Sep 2;108(9):1070-7
references.pmid: 12912808
references.citation: J Clin Invest. 2008 Jan;118(1):183-94
references.pmid: 18079965
references.citation: Nat Protoc. 2007;2(3):481-5
references.pmid: 17406610
references.citation: Mol Cell Biochem. 2010 Dec;345(1-2):189-95
references.pmid: 20714791
references.citation: Nature. 2002 Dec 19-26;420(6917):868-74
references.pmid: 12490960
references.citation: Arterioscler Thromb Vasc Biol. 2007 Aug;27(8):1706-21
references.pmid: 17541027
references.citation: Cell Tissue Res. 2011 Dec;346(3):361-8
references.pmid: 22113336
references.citation: Nature. 2002 Jul 11;418(6894):191-5
references.pmid: 12110890