(Circulation. 2001;103:2598.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Simvastatin Exerts Both Anti-inflammatory and Cardioprotective Effects in Apolipoprotein E–Deficient Mice
From the Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pa (R.S., A.M.L.); the Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, La (M.E.G., S.P.J., M.H., D.M.R., S.D.T., M.B.S., D.J.L.); and the Cardiovascular Research Center, Harvard Medical School, Massachusetts General Hospital, Charlestown, Mass (P.L.H.).
Correspondence to David J. Lefer, PhD, Department of Physiology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130. E-mail dlefer{at}lsuhsc.edu
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.
Key Words: endothelium • hypercholesterolemia • reperfusion • nitric oxide
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