Rosuvastatin restores superoxide dismutase expression and inhibits accumulation of oxidized LDL in the aortic arch of obese dyslipidemic mice.
OBJECTIVE
Our goal was to elucidate mechanisms of the inhibitory effect of rosuvastatin on the accumulation of plaque oxidized low density lipoproteins (oxLDL) and on plaque volume, without lowering cholesterol, in mice with combined leptin and LDL-receptor deficiency (DKO).


METHODS
Twelve-week old DKO mice were treated with rosuvastatin (10 mg kg(-1) day(-1), s.c.) or placebo or no treatment for 12 weeks. The effect on blood variables, aortic plaque volume and composition and gene expression in the aorta and in THP-1 cells was assessed.


RESULTS
Rosuvastatin lowered free fatty acids (FFA), triglycerides, and increased insulin sensitivity, without affecting cholesterol. Rosuvastatin lowered the plaque volume, inhibited macrophage, lipid and oxLDL accumulation, and decreased the oxLDL-to-LDL ratio of plaques in the aortic arch. It increased superoxide dismutase 1 (SOD1), CD36, LXR-alpha, ABCA-1 and PPAR-gamma RNA expression in aortic extracts. SOD1 was the strongest inverse correlate of oxLDL. In THP-1 macrophages and foam cells, expression of SOD1 was lower than in THP-1 monocytes. Rosuvastatin restored expression of SOD1 in THP-1 macrophages and foam cells.


CONCLUSIONS
Rosuvastatin restored SOD1 expression in THP-1 macrophages and foam cells in vitro and in the aorta of DKO mice. The latter was associated with less oxLDL accumulation within atherosclerotic plaques and inhibition of plaque progression. This effect was obtained at a dose not affecting cholesterol levels but improving insulin sensitivity. SOD1 is a potentially important mediator of the prevention of oxLDL accumulation within atherosclerotic plaques.
Verreth
W
W
Atherosclerosis and Metabolism Unit, Department of Cardiovascular Diseases, Katholieke Universiteit, Leuven, Belgium.
De Keyzer
D
D
Davey
P C
PC
Geeraert
B
B
Mertens
A
A
Herregods
M-C
MC
Smith
G
G
Desjardins
F
F
Balligand
J-L
JL
Holvoet
P
P
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D002460:Cell Line; D050171:Dyslipidemias / Q000097:blood / Q000235:genetics / Q000503:physiopathology; D005464:Fluorobenzenes / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000172:deficiency / Q000235:genetics; D008055:Lipids / Q000097:blood; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D009765:Obesity / Q000097:blood / Q000235:genetics / Q000503:physiopathology; D047495:PPAR gamma / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology*; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*
D001786:Blood Glucose; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007328:Insulin; D020738:Leptin; D008055:Lipids; D008077:Lipoproteins, LDL; D047495:PPAR gamma; D011743:Pyrimidines; D011973:Receptors, LDL; D013449:Sulfonamides; C099252:oxidized low density lipoprotein; D000068718:Rosuvastatin Calcium; D013482:Superoxide Dismutase