Effects of simvastatin on plasma lipoproteins and response to arterial injury in wild-type and apolipoprotein-E-deficient mice.
OBJECTIVE
To test the non-lipid-lowering effects of simvastatin on the response to injury in normolipidemic and hyperlipidemic mice.


RESULTS
Wild-type (WT) mice (n = 40) and hyperlipidemic apolipoprotein-E-deficient (apoE(-/-)) mice (n = 40) received normal chow or chow containing simvastatin 100 mg/kg/day prior to bilateral femoral artery wire injury. Intimal hyperplasia and plasma cholesterol concentration were quantified after 4 weeks. Plasma cholesterol in WT mice treated or untreated with simvastatin was similar (100.9 +/- 6.6 vs. 94.3 +/- 17.5 mg/dl). Simvastatin did not affect intimal hyperplasia. In apoE(-/-) mice, intimal hyperplasia was increased 2.3-fold relative to WT mice (17090 +/- 4998 vs. 39490 +/- 16190; p < 0.001). In apoE(-/- )mice, simvastatin caused a paradoxical increase in plasma cholesterol (1094 +/- 60.3 vs. 658 +/- 66.8 mg/dl; p < 0.001), confirmed by FPLC. This was associated with a further increase in intimal area (39490 +/- 16190 vs. 55420 +/- 22590 mm(2); p < 0.01).


CONCLUSIONS
(1). Simvastatin had no effect on plasma cholesterol or the response to arterial injury in normolipidemic WT mice; (2). hyperlipidemia was associated with markedly increased intimal hyperplasia, and (3). simvastatin treatment of apoE(-/-) mice caused paradoxical hyperlipidemia and increased intimal hyperplasia.
Choudhury
Robin P
RP
Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA. robin.choudhury@cardiov.ox.ac.uk
Carrelli
Angela L
AL
Stern
Joshua D
JD
Chereshnev
Igor
I
Soccio
Raymond
R
Elmalem
Valerie I
VI
Fallon
John T
JT
Fisher
Edward A
EA
Reis
Ernane D
ED
D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D005263:Femoral Artery / Q000293:injuries* / Q000473:pathology; D006949:Hyperlipidemias / Q000188:drug therapy* / Q000235:genetics; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008074:Lipoproteins / Q000097:blood; D051379:Mice; D008817:Mice, Mutant Strains; D019821:Simvastatin / Q000494:pharmacology*; D017539:Tunica Intima / Q000473:pathology
D001057:Apolipoproteins E; D000960:Hypolipidemic Agents; D008074:Lipoproteins; D019821:Simvastatin