Document Detail


Simvastatin exerts both anti-inflammatory and cardioprotective effects in apolipoprotein E-deficient mice.
MedLine Citation:
PMID:  11382730     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Simvastatin attenuates ischemia and reperfusion in normocholesterolemic animals by stabilizing endothelial nitric oxide synthase activity and inhibiting neutrophil-mediated injury. Because endothelial dysfunction is a detrimental effect of hypercholesterolemia, we examined whether short-term treatment with simvastatin could inhibit leukocyte-endothelium interaction and attenuate myocardial ischemia-reperfusion injury in apoE-deficient (apoE(-/-)) mice fed a high-cholesterol diet. METHODS AND RESULTS: We studied leukocyte-endothelium interactions in apoE(-/-) mice fed a normal or a high-cholesterol diet after short-term (ie, 18 hours) simvastatin treatment. We also studied simvastatin treatment in myocardial ischemia-reperfusion injury by subjecting apoE(-/-) mice to 30 minutes of ischemia and 24 hours of reperfusion. ApoE(-/-) mice fed a high-cholesterol diet exhibited higher blood cholesterol levels, which were not affected by short-term simvastatin treatment. However, the increased leukocyte rolling and adherence that occurred in cholesterol-fed apoE(-/-) mice (P<0.001 versus control diet) were significantly attenuated by simvastatin treatment (P<0.01 versus vehicle). Cholesterol-fed apoE(-/-) mice subjected to myocardial ischemia-reperfusion also experienced increased myocardial necrosis (P<0.01 versus control diet), which was significantly attenuated by simvastatin (P<0.01 versus vehicle). Simvastatin therapy also significantly increased vascular nitric oxide production in apoE(-/-) mice. CONCLUSIONS: Simvastatin attenuates leukocyte-endothelial cell interactions and ameliorates ischemic injury in hypercholesterolemic mice independently of lipid-lowering actions.
Authors:
R Scalia; M E Gooszen; S P Jones; M Hoffmeyer; D M Rimmer; S D Trocha; P L Huang; M B Smith; A M Lefer; D J Lefer
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Circulation     Volume:  103     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2001 May 
Date Detail:
Created Date:  2001-05-30     Completed Date:  2001-07-19     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2598-603     Citation Subset:  AIM; IM    
Affiliation:
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Anti-Inflammatory Agents / pharmacology*
Anticholesteremic Agents / pharmacology*
Apolipoproteins E / deficiency*,  genetics
Cardiovascular Agents / pharmacology*
Cell Adhesion / drug effects
Cell Communication / drug effects
Cholesterol / blood
Cholesterol, Dietary / administration & dosage
Endothelium, Vascular / cytology,  drug effects,  metabolism
Genotype
Heart Ventricles / drug effects,  pathology
Leukocytes / cytology,  drug effects
Mice
Mice, Mutant Strains
Myocardial Ischemia / complications
Myocardial Reperfusion Injury / etiology,  prevention & control
Neutrophils / drug effects,  pathology
Nitric Oxide / metabolism
Simvastatin / pharmacology*
Grant Support
ID/Acronym/Agency:
P01-DK-43785/DK/NIDDK NIH HHS; R01-HL-60849/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Anti-Inflammatory Agents; 0/Anticholesteremic Agents; 0/Apolipoproteins E; 0/Cardiovascular Agents; 0/Cholesterol, Dietary; 10102-43-9/Nitric Oxide; 57-88-5/Cholesterol; 79902-63-9/Simvastatin

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