Expression of alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein and scavenger receptor in human atherosclerotic lesions.

doi:10.1172/JCI117195

J Clin Invest. 1994 May; 93(5): 2014–2021.

doi: 10.1172/JCI117195.

PMCID: PMC294312

Expression of alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein and scavenger receptor in human atherosclerotic lesions.

J Luoma, T Hiltunen, T Särkioja, S K Moestrup, J Gliemann, T Kodama, T Nikkari, and S Ylä-Herttuala

Department of Biomedical Sciences, University of Tampere, Finland.

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Abstract

Macrophage- and smooth muscle cell (SMC)-derived foam cells are typical constituents of human atherosclerotic lesions. At least three receptor systems have been characterized that could be involved in the development of foam cells: alpha 2-macroglobulin receptor/LDL receptor-related protein (alpha 2 MR/LRP), scavenger receptor, and LDL receptor. We studied the expression of these receptors in human atherosclerotic lesions with in situ hybridization and immunocytochemistry. An abundant expression of alpha 2MR/LRP mRNA and protein was found in SMC and macrophages in both early and advanced lesions in human aortas. alpha 2MR/LRP was also present in SMC in normal aortas. Scavenger receptor mRNA and protein were expressed in lesion macrophages but no expression was found in lesion SMC. LDL receptor was absent from the lesion area but was expressed in some aortas in medial SMC located near the adventitial border. The results demonstrate that (a) alpha 2MR/LRP is, so far, the only lipoprotein receptor expressed in lesions SMC in vivo; (b) scavenger receptors are expressed only in lesion macrophages; and (c) both receptors may play important roles in the development of human atherosclerotic lesions.

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Ross, R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993 Apr 29;362(6423):801–809. [PubMed]
Brown, MS; Goldstein, JL. Lipoprotein metabolism in the macrophage: implications for cholesterol deposition in atherosclerosis. Annu Rev Biochem. 1983;52:223–261. [PubMed]
Steinberg, D; Parthasarathy, S; Carew, TE; Khoo, JC; Witztum, JL. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med. 1989 Apr 6;320(14):915–924. [PubMed]
Kodama, T; Freeman, M; Rohrer, L; Zabrecky, J; Matsudaira, P; Krieger, M. Type I macrophage scavenger receptor contains alpha-helical and collagen-like coiled coils. Nature. 1990 Feb 8;343(6258):531–535. [PubMed]
Matsumoto, A; Naito, M; Itakura, H; Ikemoto, S; Asaoka, H; Hayakawa, I; Kanamori, H; Aburatani, H; Takaku, F; Suzuki, H, et al. Human macrophage scavenger receptors: primary structure, expression, and localization in atherosclerotic lesions. Proc Natl Acad Sci U S A. 1990 Dec;87(23):9133–9137. [PubMed]
Ylä-Herttuala, S; Rosenfeld, ME; Parthasarathy, S; Sigal, E; Särkioja, T; Witztum, JL; Steinberg, D. Gene expression in macrophage-rich human atherosclerotic lesions. 15-lipoxygenase and acetyl low density lipoprotein receptor messenger RNA colocalize with oxidation specific lipid-protein adducts. J Clin Invest. 1991 Apr;87(4):1146–1152. [PubMed]
Naito, M; Suzuki, H; Mori, T; Matsumoto, A; Kodama, T; Takahashi, K. Coexpression of type I and type II human macrophage scavenger receptors in macrophages of various organs and foam cells in atherosclerotic lesions. Am J Pathol. 1992 Sep;141(3):591–599. [PubMed]
Herz, J; Hamann, U; Rogne, S; Myklebost, O; Gausepohl, H; Stanley, KK. Surface location and high affinity for calcium of a 500-kd liver membrane protein closely related to the LDL-receptor suggest a physiological role as lipoprotein receptor. EMBO J. 1988 Dec 20;7(13):4119–4127. [PubMed]
Kristensen, T; Moestrup, SK; Gliemann, J; Bendtsen, L; Sand, O; Sottrup-Jensen, L. Evidence that the newly cloned low-density-lipoprotein receptor related protein (LRP) is the alpha 2-macroglobulin receptor. FEBS Lett. 1990 Dec 10;276(1-2):151–155. [PubMed]
Strickland, DK; Ashcom, JD; Williams, S; Burgess, WH; Migliorini, M; Argraves, WS. Sequence identity between the alpha 2-macroglobulin receptor and low density lipoprotein receptor-related protein suggests that this molecule is a multifunctional receptor. J Biol Chem. 1990 Oct 15;265(29):17401–17404. [PubMed]
Herz, J; Kowal, RC; Goldstein, JL; Brown, MS. Proteolytic processing of the 600 kd low density lipoprotein receptor-related protein (LRP) occurs in a trans-Golgi compartment. EMBO J. 1990 Jun;9(6):1769–1776. [PubMed]
Moestrup, SK; Gliemann, J; Pallesen, G. Distribution of the alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein in human tissues. Cell Tissue Res. 1992 Sep;269(3):375–382. [PubMed]
Herz, J; Clouthier, DE; Hammer, RE. LDL receptor-related protein internalizes and degrades uPA-PAI-1 complexes and is essential for embryo implantation. Cell. 1992 Oct 30;71(3):411–421. [PubMed]
Moestrup, SK; Gliemann, J. Analysis of ligand recognition by the purified alpha 2-macroglobulin receptor (low density lipoprotein receptor-related protein). Evidence that high affinity of alpha 2-macroglobulin-proteinase complex is achieved by binding to adjacent receptors. J Biol Chem. 1991 Jul 25;266(21):14011–14017. [PubMed]
Moestrup, SK; Christensen, EI; Sottrup-Jensen, L; Gliemann, J. Binding and receptor-mediated endocytosis of pregnancy zone protein-proteinase complex in rat macrophages. Biochim Biophys Acta. 1987 Oct 1;930(3):297–303. [PubMed]
Nykjaer, A; Petersen, CM; Møller, B; Jensen, PH; Moestrup, SK; Holtet, TL; Etzerodt, M; Thøgersen, HC; Munch, M; Andreasen, PA, et al. Purified alpha 2-macroglobulin receptor/LDL receptor-related protein binds urokinase.plasminogen activator inhibitor type-1 complex. Evidence that the alpha 2-macroglobulin receptor mediates cellular degradation of urokinase receptor-bound complexes. J Biol Chem. 1992 Jul 25;267(21):14543–14546. [PubMed]
Orth, K; Madison, EL; Gething, MJ; Sambrook, JF; Herz, J. Complexes of tissue-type plasminogen activator and its serpin inhibitor plasminogen-activator inhibitor type 1 are internalized by means of the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7422–7426. [PubMed]
Kounnas, MZ; Morris, RE; Thompson, MR; FitzGerald, DJ; Strickland, DK; Saelinger, CB. The alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein binds and internalizes Pseudomonas exotoxin A. J Biol Chem. 1992 Jun 25;267(18):12420–12423. [PubMed]
Moestrup, SK; Holtet, TL; Etzerodt, M; Thøgersen, HC; Nykjaer, A; Andreasen, PA; Rasmussen, HH; Sottrup-Jensen, L; Gliemann, J. Alpha 2-macroglobulin-proteinase complexes, plasminogen activator inhibitor type-1-plasminogen activator complexes, and receptor-associated protein bind to a region of the alpha 2-macroglobulin receptor containing a cluster of eight complement-type repeats. J Biol Chem. 1993 Jun 25;268(18):13691–13696. [PubMed]
LaMarre, J; Hayes, MA; Wollenberg, GK; Hussaini, I; Hall, SW; Gonias, SL. An alpha 2-macroglobulin receptor-dependent mechanism for the plasma clearance of transforming growth factor-beta 1 in mice. J Clin Invest. 1991 Jan;87(1):39–44. [PubMed]
Stouffer, GA; LaMarre, J; Gonias, SL; Owens, GK. Activated alpha 2-macroglobulin and transforming growth factor-beta 1 induce a synergistic smooth muscle cell proliferative response. J Biol Chem. 1993 Aug 25;268(24):18340–18344. [PubMed]
Beisiegel, U; Weber, W; Ihrke, G; Herz, J; Stanley, KK. The LDL-receptor-related protein, LRP, is an apolipoprotein E-binding protein. Nature. 1989 Sep 14;341(6238):162–164. [PubMed]
Kowal, RC; Herz, J; Goldstein, JL; Esser, V; Brown, MS. Low density lipoprotein receptor-related protein mediates uptake of cholesteryl esters derived from apoprotein E-enriched lipoproteins. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5810–5814. [PubMed]
Beisiegel, U; Weber, W; Bengtsson-Olivecrona, G. Lipoprotein lipase enhances the binding of chylomicrons to low density lipoprotein receptor-related protein. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8342–8346. [PubMed]
Chappell, DA; Fry, GL; Waknitz, MA; Muhonen, LE; Pladet, MW; Iverius, PH; Strickland, DK. Lipoprotein lipase induces catabolism of normal triglyceride-rich lipoproteins via the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor in vitro. A process facilitated by cell-surface proteoglycans. J Biol Chem. 1993 Jul 5;268(19):14168–14175. [PubMed]
Nykjaer, A; Bengtsson-Olivecrona, G; Lookene, A; Moestrup, SK; Petersen, CM; Weber, W; Beisiegel, U; Gliemann, J. The alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein binds lipoprotein lipase and beta-migrating very low density lipoprotein associated with the lipase. J Biol Chem. 1993 Jul 15;268(20):15048–15055. [PubMed]
Ylä-Herttuala, S; Rosenfeld, ME; Parthasarathy, S; Glass, CK; Sigal, E; Witztum, JL; Steinberg, D. Colocalization of 15-lipoxygenase mRNA and protein with epitopes of oxidized low density lipoprotein in macrophage-rich areas of atherosclerotic lesions. Proc Natl Acad Sci U S A. 1990 Sep;87(18):6959–6963. [PubMed]
Ylä-Herttuala, S; Lipton, BA; Rosenfeld, ME; Goldberg, IJ; Steinberg, D; Witztum, JL. Macrophages and smooth muscle cells express lipoprotein lipase in human and rabbit atherosclerotic lesions. Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):10143–10147. [PubMed]
Yamamoto, T; Davis, CG; Brown, MS; Schneider, WJ; Casey, ML; Goldstein, JL; Russell, DW. The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA. Cell. 1984 Nov;39(1):27–38. [PubMed]
Raychowdhury, R; Niles, JL; McCluskey, RT; Smith, JA. Autoimmune target in Heymann nephritis is a glycoprotein with homology to the LDL receptor. Science. 1989 Jun 9;244(4909):1163–1165. [PubMed]
Takahashi, S; Kawarabayasi, Y; Nakai, T; Sakai, J; Yamamoto, T. Rabbit very low density lipoprotein receptor: a low density lipoprotein receptor-like protein with distinct ligand specificity. Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):9252–9256. [PubMed]
Moestrup, SK; Kaltoft, K; Petersen, CM; Pedersen, S; Gliemann, J; Christensen, EI. Immunocytochemical identification of the human alpha 2-macroglobulin receptor in monocytes and fibroblasts: monoclonal antibodies define the receptor as a monocyte differentiation antigen. Exp Cell Res. 1990 Oct;190(2):195–203. [PubMed]
Gown, AM; Tsukada, T; Ross, R. Human atherosclerosis. II. Immunocytochemical analysis of the cellular composition of human atherosclerotic lesions. Am J Pathol. 1986 Oct;125(1):191–207. [PubMed]
Tsukada, T; Tippens, D; Gordon, D; Ross, R; Gown, AM. HHF35, a muscle-actin-specific monoclonal antibody. I. Immunocytochemical and biochemical characterization. Am J Pathol. 1987 Jan;126(1):51–60. [PubMed]
Young, SG; Witztum, JL; Casal, DC; Curtiss, LK; Bernstein, S. Conservation of the low density lipoprotein receptor-binding domain of apoprotein B. Demonstration by a new monoclonal antibody, MB47. Arteriosclerosis. 1986 6(2):178–188.Mar–Apr; [PubMed]
Rosenfeld, ME; Palinski, W; Ylä-Herttuala, S; Butler, S; Witztum, JL. Distribution of oxidation specific lipid-protein adducts and apolipoprotein B in atherosclerotic lesions of varying severity from WHHL rabbits. Arteriosclerosis. 1990 10(3):336–349.May–Jun; [PubMed]
Swanson, LW; Simmons, DM; Hofmann, SL; Goldstein, JL; Brown, MS. Localization of mRNA for low density lipoprotein receptor and a cholesterol synthetic enzyme in rabbit nervous system by in situ hybridization. Proc Natl Acad Sci U S A. 1988 Dec;85(24):9821–9825. [PubMed]
Fong, LG; Bonney, E; Kosek, JC; Cooper, AD. Immunohistochemical localization of low density lipoprotein receptors in adrenal gland, liver, and intestine. J Clin Invest. 1989 Sep;84(3):847–856. [PubMed]
Sparrow, CP; Parthasarathy, S; Steinberg, D. A macrophage receptor that recognizes oxidized low density lipoprotein but not acetylated low density lipoprotein. J Biol Chem. 1989 Feb 15;264(5):2599–2604. [PubMed]
Ylä-Herttuala, S; Jaakkola, O; Ehnholm, C; Tikkanen, MJ; Solakivi, T; Särkioja, T; Nikkari, T. Characterization of two lipoproteins containing apolipoproteins B and E from lesion-free human aortic intima. J Lipid Res. 1988 May;29(5):563–572. [PubMed]
O'Brien, KD; Gordon, D; Deeb, S; Ferguson, M; Chait, A. Lipoprotein lipase is synthesized by macrophage-derived foam cells in human coronary atherosclerotic plaques. J Clin Invest. 1992 May;89(5):1544–1550. [PubMed]
Babaev, VR; Dergunov, AD; Chenchik, AA; Tararak, EM; Yanushevskaya, EV; Trakht, IN; Sorg, C; Smirnov, VN. Localization of apolipoprotein E in normal and atherosclerotic human aorta. Atherosclerosis. 1990 Dec;85(2-3):239–247. [PubMed]
Rosenfeld, ME; Butler, S; Ord, VA; Lipton, BA; Dyer, CA; Curtiss, LK; Palinski, W; Witztum, JL. Abundant expression of apoprotein E by macrophages in human and rabbit atherosclerotic lesions. Arterioscler Thromb. 1993 Sep;13(9):1382–1389. [PubMed]
Stein, O; Ben-Naim, M; Dabach, Y; Hollander, G; Halperin, G; Stein, Y. Can lipoprotein lipase be the culprit in cholesteryl ester accretion in smooth muscle cells in atheroma? Atherosclerosis. 1993 Feb;99(1):15–22. [PubMed]
Hoff, HF; Jackson, RL; Mao, SJ; Gotto, AM., Jr Localization of low-density lipoproteins in atherosclerotic lesions from human normolipemics employing a purified fluorescent-labeled antibody. Biochim Biophys Acta. 1974 Jun 7;351(2):407–415. [PubMed]
Freeman, M; Ekkel, Y; Rohrer, L; Penman, M; Freedman, NJ; Chisolm, GM; Krieger, M. Expression of type I and type II bovine scavenger receptors in Chinese hamster ovary cells: lipid droplet accumulation and nonreciprocal cross competition by acetylated and oxidized low density lipoprotein. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4931–4935. [PubMed]
LaMarre, J; Wolf, BB; Kittler, EL; Quesenberry, PJ; Gonias, SL. Regulation of macrophage alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein by lipopolysaccharide and interferon-gamma. J Clin Invest. 1993 Mar;91(3):1219–1224. [PubMed]
Fogelman, AM; Haberland, ME; Seager, J; Hokom, M; Edwards, PA. Factors regulating the activities of the low density lipoprotein receptor and the scavenger receptor on human monocyte-macrophages. J Lipid Res. 1981 Sep;22(7):1131–1141. [PubMed]
Rosenfeld, ME; Ylä-Herttuala, S; Lipton, BA; Ord, VA; Witztum, JL; Steinberg, D. Macrophage colony-stimulating factor mRNA and protein in atherosclerotic lesions of rabbits and humans. Am J Pathol. 1992 Feb;140(2):291–300. [PubMed]
Clinton, SK; Underwood, R; Hayes, L; Sherman, ML; Kufe, DW; Libby, P. Macrophage colony-stimulating factor gene expression in vascular cells and in experimental and human atherosclerosis. Am J Pathol. 1992 Feb;140(2):301–316. [PubMed]
Hussaini, IM; Srikumar, K; Quesenberry, PJ; Gonias, SL. Colony-stimulating factor-1 modulates alpha 2-macroglobulin receptor expression in murine bone marrow macrophages. J Biol Chem. 1990 Nov 15;265(32):19441–19446. [PubMed]
Ishibashi, S; Inaba, T; Shimano, H; Harada, K; Inoue, I; Mokuno, H; Mori, N; Gotoda, T; Takaku, F; Yamada, N. Monocyte colony-stimulating factor enhances uptake and degradation of acetylated low density lipoproteins and cholesterol esterification in human monocyte-derived macrophages. J Biol Chem. 1990 Aug 25;265(24):14109–14117. [PubMed]
Hansson, GK; Holm, J; Jonasson, L. Detection of activated T lymphocytes in the human atherosclerotic plaque. Am J Pathol. 1989 Jul;135(1):169–175. [PubMed]
Ylä-Herttuala, S. Gene expression in atherosclerotic lesions. Herz. 1992 Oct;17(5):270–276. [PubMed]
Herz, J; Goldstein, JL; Strickland, DK; Ho, YK; Brown, MS. 39-kDa protein modulates binding of ligands to low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor. J Biol Chem. 1991 Nov 5;266(31):21232–21238. [PubMed]