Rosuvastatin Activates ATP-Binding Cassette Transporter A1–Dependent Efflux Ex Vivo and Promotes Reverse Cholesterol Transport in Macrophage Cells in Mice Fed a High-Fat Diet

Abstract

Objective— It is controversial whether statins improve high-density lipoprotein (HDL) function, which plays an important role in reverse cholesterol transport in vivo. The aim of the present study was to clarify the effects of rosuvastatin and atorvastatin on reverse cholesterol transport in macrophage cells in vivo and their underlying mechanisms. Approach and Results— Male C57BL mice were divided into 3 groups (rosuvastatin, atorvastatin, and control groups) and orally administered rosuvastatin, atorvastatin, or placebo for 6 weeks under feeding with a 0.5% cholesterol+10% coconut oil diet. After administration, although there were no changes in plasma HDL cholesterol levels among the groups, plasma from the rosuvastatin group showed an increased ability to promote ATP-binding cassette transporter A1–mediated cholesterol efflux ex vivo. In addition, capillary electrophoresis revealed a shift in HDL toward the pre-β HDL fraction only in the rosuvastatin group. Mice in all 3 groups were intraperitoneally injected with 3 H-cholesterol–labeled and cholesterol-loaded macrophages and then were monitored for the appearance of 3 H-tracer in plasma and feces. The amount of 3 H-tracer excreted into feces during 48 hours in the rosuvastatin group was greater than that in the control group. Finally, 3 H-cholesteryl oleate-HDL was intravenously injected into all groups, blood samples were taken, and the count of 3 H-cholesterol was analyzed. Plasma 3 H-cholesteryl oleate-HDL changed similarly, and no differences in fractional catabolic rates were observed. Conclusions— Rosuvastatin enhanced the ATP-binding cassette transporter A1–dependent HDL efflux function of reverse cholesterol transport, and this finding highlights the potential of rosuvastatin for the regression of atherosclerosis.

Rosuvastatin Reduces Aortic Sinus and Coronary Artery Atherosclerosis in SR-B1 (Scavenger Receptor Class B Type 1)/ApoE (Apolipoprotein E) Double Knockout Mice Independently of Plasma Cholesterol Lowering

“…Various studies have reported different effects of treatment with statins, including rosuvastatin, on plasma and lipoprotein cholesterol levels in apoE −/− and other mice. 6 – 10 , 12 , 17 – 23 , 64 For example, some reported reductions in plasma cholesterol levels, 7 , 8 , 64 whereas others reported unaltered plasma cholesterol and triglyceride levels 6 , 9 , 10 , 12 , 17 – 20 , 65 , 66 in apoE −/− and other mice treated with rosuvastatin. Still other studies reported that treatment of apoE −/− mice with other statins, including simvastatin, resulted in increased plasma cholesterol levels, in some cases accompanied by increased atherosclerosis.…”

“… 14 – 16 Several studies demonstrated that rosuvastatin treatment at varying doses reduced inflammation, thrombosis, and apoptosis in the aortic sinus and proximal aortas of apoE −/− mice, although plasma total cholesterol and triglyceride levels were not altered. 6 , 9 , 10 , 12 , 17 – 20 On the other hand, other studies reported beneficial effects of rosuvastatin were accompanied by reductions in plasma total cholesterol in apoE −/− mice. 7 , 8 Still, other studies have reported that treatment of apoE −/− mice with other statins, including simvastatin, resulted in increased plasma cholesterol levels in some cases accompanied by increased atherosclerosis.…”

Niacin Therapy Increases High-Density Lipoprotein Particles and Total Cholesterol Efflux Capacity But Not ABCA1-Specific Cholesterol Efflux in Statin-Treated Subjects

“…In mouse studies rosuvastatin treatment enhanced ABCA1-specific cholesterol efflux capacity, but atorvastatin had no effect. 29 A small study showed that pitavastatin increased cholesterol efflux capacity from human macrophages by 8.6%. 30 In the JUPITER trial (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin), rosuvastatin treatment increased HDL-C by 6%.…”

High density lipoproteins: Measurement techniques and potential biomarkers of cardiovascular risk

“…Also, this technique can separate charge based LDL subfractions in (fast, slow and minor) with a drop of plasma and within minutes [84] . This technique is reported in CAD clinical trial testing drugs that raise HDL-C levels [85] , [86] , or in evaluating mechanism of apoA-I mimetic peptides in plasma [87] , [88] or also in some clinical laboratories as routine analytical assay [82] . Importantly, in patient with hypercholesterolemia the charge-modified LDL subfraction as determined by cITP (fLDL) subfraction is suggested as a possible potential useful biomarker for the risk of CAD [89] .…”