Human macrophage scavenger receptors: primary structure, expression, and localization in atherosclerotic lesions.

Abstract

Two types of cDNAs for human macrophage scavenger receptors were cloned from a cDNA library derived from the phorbol ester-treated human monocytic cell line THP-1. The type I and type II human scavenger receptors encoded by these cDNAs are homologous (73% and 71% amino acid identity) to their previously characterized bovine counterparts and consist of six domains: cytoplasmic (I), membrane-spanning (II), spacer (Ill), ae-helical coiled-coil (IV), collagen-like (V), and a type-specific C-terminal (VI). The receptor gene is located on human chromosome 8. The human receptors expressed in CHO-K1 cells mediated endocytosis of modified low density lipoproteins. Two mRNAs, 4.0 and 3.2 kiobases, have been detected in human liver, placenta, and brain. Immunohistochemical studies using an anti-peptide antibody which recognizes human scavenger receptors indicated the presence of the scavenger receptors in the macrophages of lipid-rich atherosclerotic lesions, suggesting the involvement of scavenger receptors in atherogenesis.The macrophage scavenger receptors are trimeric membrane glycoproteins implicated in the pathologic deposition of cholesterol in arterial walls during atherogenesis (1,2). The molecular cloning of bovine scavenger receptor cDNAs has revealed several unexpected features (3, 4). Two types of receptor subunits exist, and both of these receptor proteins contain two extracellular domains that are predicted to form a long triple-stranded a-helical coiled coil and a collagen-like triple helix (3, 4). These receptors mediate the endocytosis of a diverse group of macromolecules, including modified low density lipoproteins (LDLs) (1-5). When cultured macrophages are exposed to appropriately modified LDLs, they are converted to cholesteryl ester-rich foam cells which are strikingly similar to the foam cells found in atherosclerotic plaques (1). Recent in vivo studies support the suggestion that modified LDLs, possibly internalized via the scavenger receptors, may play a critical role in the development of atherosclerosis (6)(7)(8).To study the role of human scavenger receptors in atherogenesis, we have cloned human scavenger receptor cDNAs.tt From the deduced amino acid sequence, we generated rabbit anti-peptide antiserum that recognizes human macrophage receptors. Immunohistochemical studies using this antibody have revealed the presence of immunoreactive scavenger receptor protein in the macrophages ofatherosclerotic lesions, suggesting the involvement of scavenger receptors in atherogenesis. MATERIALS AND METHODSMolecular Cloning of Human Scavenger Receptor cDNAs. THP-1 cells were cultivated in the presence of 200 nM phorbol 12-myristate 13-acetate (PMA) for 4 days (2). Poly(A)+ RNA was isolated from these cells and was used to construct a size-fractionated oligo(dT)-primed cDNA library in A ZAP 11 (3). The Xba I-Sph I fragment of pBSR7 corresponding to the collagen-like domain of the bovine receptor (3) labeled by random priming was used as a hybridization probe to screen 6 x 105 plaques. Two positive...

Expression of receptors for native and chemically modified low‐density lipoproteins in brain microvessels

“…In particular, the presence of SCAV-Rs in total brain had been detected in bovine brain by some authors [13] but not by others, and Northern blot analysis performed with specific probes for SCAV-Rs type I [5] or type II [6] had failed to show any expression in bovine brain. The discrepancy between these negative results in total brain and our positive findings in cerebral microvessels can reasonably be ascribed to quantitative differences in the relative amounts of mRNA for SCAV-Rs, as well as to the higher sensitivity of RT-PCR with respect to Northern blot analysis.…”

“…E-mail: luc@dbu.uniromal.it Abbreviations: AcLDL, acetylated low-density lipoprotein; BBB, blood-brain barrier; CNS, central nervous system; Ecs, endothelial cells; LDL, low-density lipoprotein; LDL-R, low-density lipoprotein receptor; OxLDL, oxidized low-density lipoprotein; RT, reverse transcriptase; SCAV-R, scavenger receptor; SMCs, smooth muscle cells blotting and/or by 125 I-labeled or fluorescent modified LDL uptake, to be present in macrophages [5][6][7], in various kinds of vascular endothelial cells (Ecs) [5,6,[8][9][10], in fibroblasts and in smooth muscle cells (SMCs) [11,12]. Their presence has been reported in brain by some authors [13] but not by others [5].…”

Identification of a chromosome 8p locus for early-onset coronary heart disease in a French Canadian population

“…67 The expression of this receptor is increased in the macrophages of atherogenic lesions 68 and it plays a role in the development of foam cells. 69 Moreover, MSR1 null mice (MsrÀ/À) on a background of atherosclerosis-susceptible apoE-deficient (ApoeÀ/À) mice demonstrated significantly smaller atherosclerotic lesions compared with ApoeÀ/À littermates.…”

Dualism of Oxidized Lipoproteins in Provoking and Attenuating the Oxidative Burst in Macrophages: Role of Peroxisome Proliferator-Activated Receptor-γ

“…In addition, oxLDL is both a potent chemoattractant for circulating monocytes (8) and a differentiating agent that promotes transition of macrophages to lipid-loaded foam cells (9). In close association, receptor-mediated endocytosis of oxLDL by several scavenger receptor family members including macrophage class A scavenger receptor (10,11), CD36 (12), scavenger receptor that binds phosphatidylserine and oxidized lipoprotein (13), or lectin-like oxidized low density lipoprotein receptor-1 (14) is implicated in the process of atherogenesis. Atherosclerosis is now considered a problem of wound healing and chronic inflammation and can be viewed as a response to injury, with lipoproteins or other risk factors as the injurious agents, keeping in mind the important idea that accumulation of lipid-loaded foam cells in fatty streaks are a primary event in disease progression (15).…”