Simvastatin reduces neointimal thickening in low-density lipoprotein receptor-deficient mice after experimental angioplasty without changing plasma lipids.
BACKGROUND
Statins exert antiinflammatory and antiproliferative actions independent of cholesterol lowering. To determine whether these actions might affect neointimal formation, we investigated the effect of simvastatin on the response to experimental angioplasty in LDL receptor-deficient (LDLR-/-) mice, a model of hypercholesterolemia in which changes in plasma lipids are not observed in response to simvastatin.


RESULTS
Carotid artery dilation (2.5 atm) and complete endothelial denudation were performed in male C57BL/6J LDLR-/- mice treated with low-dose (2 mg/kg) or high-dose (20 mg/kg) simvastatin or vehicle subcutaneously 72 hours before and then daily after injury. After 7 and 28 days, intimal and medial sizes were measured and the intima to media area ratio (I:M) was calculated. Total plasma cholesterol and triglyceride levels were similar in simvastatin- and vehicle-treated mice. Intimal thickening and I:M were reduced significantly by low- and high-dose simvastatin compared with vehicle alone. Simvastatin treatment was associated with reduced cellular proliferation (BrdU), leukocyte accumulation (CD45), and platelet-derived growth factor-induced phosphorylation of the survival factor Akt and increased apoptosis after injury.


CONCLUSIONS
Simvastatin modulates vascular repair after injury in the absence of lipid-lowering effects. Although the mechanisms are not yet established, additional research may lead to new understanding of the actions of statins and novel therapeutic interventions for preventing restenosis.
Chen
Zhiping
Z
Cardiovascular Division, Brigham and Women's Hospital, Boston, Mass 02115, USA.
Fukutomi
Tatsuya
T
Zago
Alexandre C
AC
Ehlers
Raila
R
Detmers
Patricia A
PA
Wright
Samuel D
SD
Rogers
Campbell
C
Simon
Daniel I
DI
D017130:Angioplasty / Q000009:adverse effects*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D017209:Apoptosis; D016893:Carotid Stenosis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement; D006083:Graft Occlusion, Vascular / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006949:Hyperlipidemias / Q000097:blood; D007962:Leukocytes / Q000502:physiology; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000235:genetics*; D019821:Simvastatin / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D011973:Receptors, LDL; D019821:Simvastatin