Simvastatin exerts both anti-inflammatory and cardioprotective effects in apolipoprotein E-deficient mice.
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.


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.
Scalia
R
R
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA.
Gooszen
M E
ME
Jones
S P
SP
Hoffmeyer
M
M
Rimmer
D M
DM
Trocha
S D
SD
Huang
P L
PL
Smith
M B
MB
Lefer
A M
AM
Lefer
D J
DJ
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D002317:Cardiovascular Agents / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002450:Cell Communication / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005838:Genotype; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008817:Mice, Mutant Strains; D017202:Myocardial Ischemia / Q000150:complications; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000517:prevention & control; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; D000924:Anticholesteremic Agents; D001057:Apolipoproteins E; D002317:Cardiovascular Agents; D002791:Cholesterol, Dietary; D009569:Nitric Oxide; D002784:Cholesterol; D019821:Simvastatin