PMID- 12818400
OWN - NLM
STAT- MEDLINE
DCOM- 20030730
LR  - 20190718
IS  - 0021-9150 (Print)
IS  - 0021-9150 (Linking)
VI  - 167
IP  - 2
DP  - 2003 Apr
TI  - Simvastatin inhibits expression of tissue factor in advanced atherosclerotic 
      lesions of apolipoprotein E deficient mice independently of lipid lowering: 
      potential role of simvastatin-mediated inhibition of Egr-1 expression and 
      activation.
PG  - 187-94
AB  - Recent studies suggest that the beneficial effects of 3-hydroxy-3-methylglutaryl 
      coenzyme A (HMG CoA) reductase inhibitors (statins) in reducing cardiovascular 
      events may in part, be independent of their capacity to lower plasma lipids. To 
      test this hypothesis, simvastatin (50 mg/kg/d) was administered to 30-week-old 
      apolipoprotein E deficient mice (apo E-/-) for 12, 18 and 24 weeks. In contrast 
      to other experimental models and humans, simvastatin treatment increases plasma 
      cholesterol levels in apo E-/- mice. Quantitative real-time polymerase chain 
      reaction was used to quantify expression of tissue factor (TF) and monocyte 
      chemoattractant protein-1 (MCP-1) in the aorta of each mouse. Expression of TF 
      was reduced to 34, 24, and 13% of control levels at 12, 18 and 24 weeks, 
      respectively, of simvastatin administration. Advanced lesions in the innominate 
      arteries of the simvastatin treated mice had reduced levels of TF, fewer 
      macrophages and reduced expression of early growth response-1 (Egr-1). In vitro 
      studies in mouse macrophages demonstrated decreased lipopolysaccharide induced 
      binding of nuclear proteins to the Egr-1 consensus DNA sequence following 
      pretreatment with simvastatin. RNA levels for MCP-1 were reduced to 30% of 
      control values following 24 weeks of simvastatin treatment. In conclusion, these 
      data suggest that chronic administration of simvastatin to older apo E-/- mice 
      can inhibit the expression of pro-thrombotic/pro-inflammatory genes within 
      established atherosclerotic lesions via mechanisms that are independent of 
      reductions in plasma lipids.
FAU - Bea, Florian
AU  - Bea F
AD  - Department of Pathobiology, Box 353410, University of Washington, Seattle, WA 
      98195, USA.
FAU - Blessing, Erwin
AU  - Blessing E
FAU - Shelley, Monica I
AU  - Shelley MI
FAU - Shultz, Jennifer M
AU  - Shultz JM
FAU - Rosenfeld, Michael E
AU  - Rosenfeld ME
LA  - eng
GR  - HL 58954/HL/NHLBI NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - Ireland
TA  - Atherosclerosis
JT  - Atherosclerosis
JID - 0242543
RN  - 0 (Apolipoproteins E)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors)
RN  - 9035-58-9 (Thromboplastin)
RN  - 97C5T2UQ7J (Cholesterol)
RN  - AGG2FN16EV (Simvastatin)
SB  - IM
MH  - Animals
MH  - Apolipoproteins E/*deficiency
MH  - Arteriosclerosis/*drug therapy/*pathology
MH  - Base Sequence
MH  - Chemokine CCL2/*analysis
MH  - Cholesterol/*analysis
MH  - Culture Techniques
MH  - Disease Models, Animal
MH  - Hydroxymethylglutaryl-CoA Reductase Inhibitors/*pharmacology
MH  - Immunohistochemistry
MH  - Male
MH  - Mice
MH  - Mice, Inbred Strains
MH  - Molecular Sequence Data
MH  - Probability
MH  - Reverse Transcriptase Polymerase Chain Reaction/methods
MH  - Sensitivity and Specificity
MH  - Severity of Illness Index
MH  - Simvastatin/*pharmacology
MH  - Thromboplastin/*analysis/drug effects
EDAT- 2003/06/24 05:00
MHDA- 2003/07/31 05:00
CRDT- 2003/06/24 05:00
PHST- 2003/06/24 05:00 [pubmed]
PHST- 2003/07/31 05:00 [medline]
PHST- 2003/06/24 05:00 [entrez]
AID - S0021-9150(02)00387-8 [pii]
AID - 10.1016/s0021-9150(02)00387-8 [doi]
PST - ppublish
SO  - Atherosclerosis. 2003 Apr;167(2):187-94. doi: 10.1016/s0021-9150(02)00387-8.