Abstract
BackgroundStatins 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.ResultsThe 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.ConclusionsWe 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.
Highlights
Statins are first-line pharmacotherapeutic agents for hypercholesterolemia treatment in humans
Simvastatin decreases atherosclerotic lesion formation in apoE-/- mice fed a high-fat diet As shown in Figure 1, administration of simvastatin with 5.0 mg/kg significantly inhibited the formation of atherosclerotic lesions in cross-sections of the aortic valve area by 35% compared with model group (Figure A and B)
Our results showed that the expressions of hepatic apolipoprotein A-I (apoA-I) and ABCA1 were increased by simvastatin treatment in vivo, these data gave us a clue that the elevated plasma HDLC level by simvastatin in this study might be closely associated with the enhanced hepatic apoA-I and ABCA1 expression stimulated by simvastatin
Summary
Statins are first-line pharmacotherapeutic agents for hypercholesterolemia treatment in humans. 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. Increased cholesterol levels have been associated with cardiovascular diseases (CVD), and statins are first-line pharmacotherapeutic agents for the treatment of these diseases in humans. Reverse cholesterol transport (RCT) is believed to be crucial for preventing atherogenesis and the development of most cardiovascular diseases. This antiatherogenic mechanism involves export of cholesterol from lipid-laden macrophages in the artery wall back to the liver for eventual excretion. We detected the effects of simvastatin on plasma LCAT activities and apoA-I concentrations, which play roles in RCT in apoE-/- mice
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