Pitavastatin Inhibits Remnant Lipoprotein-Induced Macrophage Foam Cell Formation Through ApoB48 Receptor–Dependent Mechanism

Abstract

Objective-Atherogenic remnant lipoproteins (RLPs) are known to induce foam cell formation in macrophages in vitro and in vivo. We examined the involvement of apoB48 receptor (apoB48R), a novel receptor for RLPs, in that process in vitro and its potential regulation by pitavastatin. Methods and Results-THP-1 macrophages were incubated in the presence of RLPs (20 mg cholesterol/dL, 24 hours) isolated from hypertriglyceridemic subjects. RLPs significantly increased intracellular cholesterol ester (CE) and triglyceride (TG) contents (4.8-fold and 5.8-fold, respectively) in the macrophages. Transfection of THP-1 macrophages with short interfering RNA (siRNA) against apoB48R significantly inhibited RLP-induced TG accumulation by 44%. When THP-1 macrophages were pretreated with pitavastatin (5 mol/L, 24 hours), the expression of apoB48R was significantly decreased and RLP-induced TG accumulation was reduced by 56%. ApoB48R siRNA also inhibited TG accumulation in THP-1 macrophage induced by ␤-very-low-density lipoprotein derived from apoEϪ/Ϫ mice by 58%, supporting the notion that apoB48R recognizes and takes-up RLPs in an apoE-independent manner. Key Words: remnant lipoproteins Ⅲ foam cell formation Ⅲ apoB48 receptor Ⅲ statin Ⅲ atherosclerosis C linical studies have revealed that remnant lipoproteins (RLPs), which are produced by hydrolysis of chylomicrons (CMs) and very-low-density lipoproteins (VLDL), are closely related to atherosclerosis, independent of high-density lipoprotein and low-density lipoprotein (LDL). 1,2 There is also increasing evidence that RLPs play a causative role in atherogenesis, and we recently reported that they induced monocyte-endothelial interaction and vascular smooth muscle cell proliferation. 3,4 However, the effect(s) of RLPs on cellular mechanism(s) during atherogenesis have not been fully elucidated. Conclusions-RLPsAtherogenesis involves the appearance of lipid-loaded foam cells derived from macrophages in the arterial intima. RLPs from hypertriglyceridemic VLDL and CMs cause rapid lipid accumulation, and induce foam cell formation in macrophages, whereas normal VLDL and LDL do not. 5 Thus, inhibition of macrophage foam cell formation induced by RLPs may contribute to the prevention of atherosclerosis. It has been reported that mechanisms independent of apolipoprotein (apo) E and LDL receptor family are involved in lipid accumulation in macrophages. 6 Recently, apoB48 receptor (apoB48R) was shown to be involved in the uptake of triglyceride-rich lipoproteins (TRLs) and contribute to atherogenesis, 7 although the role of apoB48R in this process remains unclear. Herein, we report for the first time to our knowledge the dominant role of apoB48R in RLP-induced foam cell formation by selective downregulation of apoB48R with short interfering RNA (siRNA).Recently, 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitor, or statin, has been suggested to have beneficial effects for the prevention of atherosclerosis, independent of its LDL cholesterol-lowering effect. 8 We found ...

Pitavastatin Improves Serum Resistin Levels in Patients with Hypercholesterolemia

“…In addition to many recent studies concerning the inhibitory effects of pitavastatin on aortic smooth muscle cells and vascular endothelial cells [17][18][19][20] , there are reports of the suppressive effects of pitavastatin on macrophage accumulation and functions. Pitavastatin enhanced the expression of SR-B in macrophages which can reduce the development of atherosclerotic lesions through the inactivation of the transcription factor NF-kappaB 13) and inhibition of the RLP-induced formation of foam cells by macrophages partly through the regulation of the apoB48 receptor 14) . A recent experimental study by Suzuki et al showed that 16 weeks of treatment with pitavastatin reduced the macrophage-positive area in the rabbit aortic plaque by 39.4% and increased the areas occupied by collagen and alpha-smooth muscle actin (alpha-SMA) by 66.4 and 91.7%, respectively 21) .…”

“…Furthermore, atherogenic remnant lipoproteins (RLPs) are known to induce foam cell formation from macrophages in vitro and in vivo. An in vitro study by Kawakami demonstrated that pitavastatin inhibited the RLP-induced formation of foam cells by macrophages, at least in part, through regulation of the involvement of the apoB48 receptor, a novel receptor for RLPs 14) . These preventative actions of pitavastatin suggested that the drug can also beneficially regulate resistin levels, which may lead to improvements in insulin resistance and atherosclerosis.…”

Remnant Lipoproteins and Atherogenesis

“…It recognizes apoB48 or its equivalent domain of apoB100 of TRLs, and takes up CM, CM remnant, HTG-VLDL, and VLDL remnant, but not nascent VLDL or LDL. We examined the involvement of apoB48 receptor in RLP-induced foam cell formation in macrophages (23). In our experiments, siRNA against apoB48 receptor significantly suppressed their expression in THP-1 macrophages, and inhibited RLP-induced foam cell formation.…”

Patients with CD36 Deficiency Are Associated with Enhanced Atherosclerotic Cardiovascular Diseases

“…Furthermore, as nicely reviewed by Fujioka et al 29) , increased remnant lipoproteins (mainly chylomicron remnants) contribute to form atherosclerotic lesions through a variety of mechanisms. It was demonstrated that chylomicron remnants invade directly into the subendothelial spaces of arteries and are taken up by macrophages via several receptors, such as LDL receptor-related protein (LRP) or apoB-48 receptor, resulting in macrophage foam cell formation [30][31][32][33] . We reported that increased serum chylomicron remnants are directly associated with enhanced carotid atherosclerosis in subjects with apparently normal TG levels 34) .…”