Simvastatin reduces atherogenesis and promotes the expression of hepatic genes associated with reverse cholesterol transport in apoE-knockout mice fed high-fat diet.
BACKGROUND
Statins are first-line pharmacotherapeutic agents for hypercholesterolemia treatment in humans. However the effects of statins on atherosclerosis in mouse models are very paradoxical. In this work, we wanted to evaluate the effects of simvastatin on serum cholesterol, atherogenesis, and the expression of several factors playing important roles in reverse cholesterol transport (RCT) in apoE-/- mice fed a high-fat diet.


RESULTS
The atherosclerotic lesion formation displayed by oil red O staining positive area was reduced significantly by 35% or 47% in either aortic root section or aortic arch en face in simvastatin administrated apoE-/- mice compared to the control. Plasma analysis by enzymatic method or ELISA showed that high-density lipoprotein-cholesterol (HDL-C) and apolipoprotein A-I (apoA-I) contents were remarkably increased by treatment with simvastatin. And plasma lecithin-cholesterol acyltransferase (LCAT) activity was markedly increased by simvastatin treatment. Real-time PCR detection disclosed that the expression of several transporters involved in reverse cholesterol transport, including macrophage scavenger receptor class B type I, hepatic ATP-binding cassette (ABC) transporters ABCG5, and ABCB4 were induced by simvastatin treatment, the expression of hepatic ABCA1 and apoA-I, which play roles in the maturation of HDL-C, were also elevated in simvastatin treated groups.


CONCLUSIONS
We demonstrated the anti-atherogenesis effects of simvastatin in apoE-/- mice fed a high-fat diet. We confirmed here for the first time simvastatin increased the expression of hepatic ABCB4 and ABCG5, which involved in secretion of cholesterol and bile acids into the bile, besides upregulated ABCA1 and apoA-I. The elevated HDL-C level, increased LCAT activity and the stimulation of several transporters involved in RCT may all contribute to the anti-atherosclerotic effect of simvastatin.
Institute of Atherosclerosis, Taishan Medical University, Taian, Shandong 271000, China.
Guohua
G
Song
Jia
J
Liu
Zhenmei
Z
Zhao
Yang
Y
Yu
Hua
H
Tian
Shutong
S
Yao
Guoli
G
Li
Shucun
S
Qin
D064286:ATP Binding Cassette Transporter 1; D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000473:pathology; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001692:Biological Transport; D002784:Cholesterol / Q000378:metabolism*; D004041:Dietary Fats / Q000008:administration & dosage*; D057075:Enzyme Assays; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000097:blood; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D015854:Up-Regulation; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D064286:ATP Binding Cassette Transporter 1; D018435:ATP Binding Cassette Transporter, Subfamily B; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D002784:Cholesterol; D004041:Dietary Fats; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008074:Lipoproteins; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D051122:Scavenger Receptors, Class B; D019821:Simvastatin; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C577836:ABCA1 protein, human; C462600:ABCG5 protein, mouse; C454739:Scarb1 protein, mouse
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