Effect of Human Scavenger Receptor Class A Overexpression in Bone Marrow–Derived Cells on Cholesterol Levels and Atherosclerosis in ApoE-Deficient Mice

Abstract

Abstract-In the arterial wall, scavenger receptor class A (SRA) is implicated in pathological lipid deposition. In contrast, in the liver, SRA is suggested to remove modified lipoproteins from the circulation, thereby protecting the body from their pathological action. The role of SRA on bone marrow-derived cells in lipid metabolism and atherogenesis was assessed in vivo by transplantation of bone marrow cells overexpressing human SRA (MSR1) to apoE-deficient mice.In vitro studies with peritoneal macrophages from the transplanted mice showed that macrophage scavenger receptor function, as measured by cell association and degradation studies with acetylated LDL, was Ϸ3-fold increased on overexpression of MSR1 in bone marrow-derived cells as compared with control mice. Despite the increased macrophage scavenger receptor function in vitro, no significant effect of MSR1 overexpression in bone marrow-derived cells on the in vivo atherosclerotic lesion development was found. In addition to arterial wall macrophages, liver sinusoidal Kupffer cells also overexpress MSR1 after bone marrow transplantation, which may scavenge atherogenic particles more efficiently from the blood compartment. Introduction of bone marrow cells overexpressing human MSR1 in apoE-deficient mice induced a significant reduction in serum cholesterol levels of Ϸ20% (PϽ0.001, 2-way ANOVA) as the result of a decrease in VLDL cholesterol. It is suggested that the reduction in VLDL cholesterol levels is due to increased Key Words: scavenger receptor Ⅲ atherosclerosis Ⅲ hyperlipidemia Ⅲ macrophages Ⅲ bone marrow transplantation A n early stage in the development of atherosclerosis is the formation of foam cells that arise from macrophages and smooth muscle cells caused by the excessive uptake of cholesteryl ester-rich lipoproteins. 1,2 Several lipoprotein receptors have been characterized that might be involved in the uptake of lipoproteins by these cell types, including the LDL receptor, the VLDL receptor, LDL receptor-related protein (LRP), and several types of scavenger receptors. 3,4 Scavenger receptor class A (SRA) was the first scavenger receptor that was identified and the molecular cloning of this receptor disclosed 2 isoforms, type I and type II, which are derived from alternative splicing of a single gene product. [5][6][7][8] SRA is a trimeric glycoprotein that consists of 6 different domains, including the isoform-specific C-terminal domain and the collagen-like domain, which is involved in ligand binding. 9 SRA mediates the uptake and degradation of a broad range of negatively charged ligands and modified lipoproteins, including oxidized and acetylated LDL (OxLDL and AcLDL). 10,11 In contrast to the LDL receptor, SRA is not downregulated by intracellular cholesteryl ester accumulation and might therefore play an important role in foam cell formation. 5 The expression of SRA in the vessel wall is highly induced during cholesterol feeding and the induction of atherosclerotic lesion formation. 3 Immunohistochemical studies in humans, rabbits, ...

Loss of receptor-mediated lipid uptake via scavenger receptor A or CD36 pathways does not ameliorate atherosclerosis in hyperlipidemic mice

“…In that study, the mean plasma cholesterol level of the Apoe -/-male mice was 935 mg/dl, which corresponds well with the value (922 mg/dl) we measured in the Apoe -/-mice used in our study. Two studies have also noted that Msr1 expression alters total cholesterol levels in the Apoe -/-mouse model; Suzuki et al showed that loss of Msr1 led to a 40% increase in total cholesterol while Van Eck et al demonstrated that overexpression of Msr1 reduced total cholesterol by a similar fraction (9,17). In addition, using SR-A transgenic mice, Wolle et al showed that overexpression of this receptor suppressed diet-induced increases in lipoproteins that contain apoB (18).…”

Visfatin induces cholesterol accumulation in macrophages through up-regulation of scavenger receptor-A and CD36

“…The aortic sinus was embedded and then made into serial cryosections of 7-μm thickness. The atherosclerotic lesions at aortic sinus were stained with ORO as previously described (Van Eck et al 2000). The mean lesion area for each mouse was calculated from four sections.…”

Berberine promotes the development of atherosclerosis and foam cell formation by inducing scavenger receptor A expression in macrophage

“…The lesion size was quantified by measuring Oil-red-O stained area. The mean lesion size for each individual mouse was calculated from four sections, starting at the appearance of the tricuspid valves [40]. SR-A in cells at atherosclerotic lesion was stained with anti-SR-A antibody.…”