Abstract
Scavenger receptor (ScR)-mediated uptake of modified lipoproteins may contribute to the transformation of smooth muscle cells into lipid-laden foam cells during atherogenesis. This study examined the in vivo expression of ScRs in aortas, with or without balloon injury, taken from hypercholesterolemic or normocholesterolemic rabbits. Numerous intimal cells in the rabbit aortic lesions expressed ScRs as detected by immunocytochemical staining with a goat anti-rabbit ScR antibody. Single immunostaining for cell identification markers in serial sections, as well as double staining, confirmed the expression of ScRs by both intimal smooth muscle cells and macrophages. To explore potential inducers of ScR expression by smooth muscle cells in vivo, we studied the regulation of ScR expression in vitro by cytokines known to be present in atherosclerotic lesions. Tumor necrosis factor-alpha (TNF-alpha) or interferon-gamma (IFN-gamma) increased ScR mRNA levels, protein expression, and AcLDL degradative activity in cultured rabbit aortic smooth muscle cells. The induction of ScR expression in intimal smooth muscle cells in vivo could be a useful marker of smooth muscle cell activation during atherogenesis and may contribute to foam cell formation by this cell type following balloon injury and/or hypercholesterolemia. Cytokines, such as TNF-alpha or IFN-gamma, may stimulate some of the phenotypic changes that characterize the alteration in gene expression of intimal smooth muscle cells in rabbit atherosclerotic lesions.
Full text
PDF











Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Acton S. L., Scherer P. E., Lodish H. F., Krieger M. Expression cloning of SR-BI, a CD36-related class B scavenger receptor. J Biol Chem. 1994 Aug 19;269(33):21003–21009. [PubMed] [Google Scholar]
- Acton S., Resnick D., Freeman M., Ekkel Y., Ashkenas J., Krieger M. The collagenous domains of macrophage scavenger receptors and complement component C1q mediate their similar, but not identical, binding specificities for polyanionic ligands. J Biol Chem. 1993 Feb 15;268(5):3530–3537. [PubMed] [Google Scholar]
- Ashkenas J., Penman M., Vasile E., Acton S., Freeman M., Krieger M. Structures and high and low affinity ligand binding properties of murine type I and type II macrophage scavenger receptors. J Lipid Res. 1993 Jun;34(6):983–1000. [PubMed] [Google Scholar]
- Babaev V. R., Bobryshev Y. V., Stenina O. V., Tararak E. M., Gabbiani G. Heterogeneity of smooth muscle cells in atheromatous plaque of human aorta. Am J Pathol. 1990 May;136(5):1031–1042. [PMC free article] [PubMed] [Google Scholar]
- Bickel P. E., Freeman M. W. Rabbit aortic smooth muscle cells express inducible macrophage scavenger receptor messenger RNA that is absent from endothelial cells. J Clin Invest. 1992 Oct;90(4):1450–1457. doi: 10.1172/JCI116012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bilheimer D. W., Eisenberg S., Levy R. I. The metabolism of very low density lipoprotein proteins. I. Preliminary in vitro and in vivo observations. Biochim Biophys Acta. 1972 Feb 21;260(2):212–221. doi: 10.1016/0005-2760(72)90034-3. [DOI] [PubMed] [Google Scholar]
- Brown M. S., Basu S. K., Falck J. R., Ho Y. K., Goldstein J. L. The scavenger cell pathway for lipoprotein degradation: specificity of the binding site that mediates the uptake of negatively-charged LDL by macrophages. J Supramol Struct. 1980;13(1):67–81. doi: 10.1002/jss.400130107. [DOI] [PubMed] [Google Scholar]
- Brown M. S., Goldstein J. L. Lipoprotein metabolism in the macrophage: implications for cholesterol deposition in atherosclerosis. Annu Rev Biochem. 1983;52:223–261. doi: 10.1146/annurev.bi.52.070183.001255. [DOI] [PubMed] [Google Scholar]
- Chap Z., Ishida T., Chou J., Lewis R., Hartley C., Entman M., Field J. B. Effects of atropine and gastric inhibitory polypeptide on hepatic glucose uptake and insulin extraction in conscious dogs. J Clin Invest. 1985 Sep;76(3):1174–1181. doi: 10.1172/JCI112073. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Clinton S. K., Underwood R., Hayes L., Sherman M. L., Kufe D. W., 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. [PMC free article] [PubMed] [Google Scholar]
- Cybulsky M. I., Gimbrone M. A., Jr Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science. 1991 Feb 15;251(4995):788–791. doi: 10.1126/science.1990440. [DOI] [PubMed] [Google Scholar]
- Doi T., Higashino K., Kurihara Y., Wada Y., Miyazaki T., Nakamura H., Uesugi S., Imanishi T., Kawabe Y., Itakura H. Charged collagen structure mediates the recognition of negatively charged macromolecules by macrophage scavenger receptors. J Biol Chem. 1993 Jan 25;268(3):2126–2133. [PubMed] [Google Scholar]
- Endemann G., Stanton L. W., Madden K. S., Bryant C. M., White R. T., Protter A. A. CD36 is a receptor for oxidized low density lipoprotein. J Biol Chem. 1993 Jun 5;268(16):11811–11816. [PubMed] [Google Scholar]
- Fogelman A. M., Haberland M. E., Seager J., Hokom M., Edwards P. A. 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] [Google Scholar]
- Fong L. G., Fong T. A., Cooper A. D. Inhibition of mouse macrophage degradation of acetyl-low density lipoprotein by interferon-gamma. J Biol Chem. 1990 Jul 15;265(20):11751–11760. [PubMed] [Google Scholar]
- Freeman M., Ashkenas J., Rees D. J., Kingsley D. M., Copeland N. G., Jenkins N. A., Krieger M. An ancient, highly conserved family of cysteine-rich protein domains revealed by cloning type I and type II murine macrophage scavenger receptors. Proc Natl Acad Sci U S A. 1990 Nov;87(22):8810–8814. doi: 10.1073/pnas.87.22.8810. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Freeman M., Ekkel Y., Rohrer L., Penman M., Freedman N. J., Chisolm G. M., 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. doi: 10.1073/pnas.88.11.4931. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gabbiani G., Kocher O., Bloom W. S., Vandekerckhove J., Weber K. Actin expression in smooth muscle cells of rat aortic intimal thickening, human atheromatous plaque, and cultured rat aortic media. J Clin Invest. 1984 Jan;73(1):148–152. doi: 10.1172/JCI111185. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Geng Y. J., Hansson G. K. Interferon-gamma inhibits scavenger receptor expression and foam cell formation in human monocyte-derived macrophages. J Clin Invest. 1992 Apr;89(4):1322–1330. doi: 10.1172/JCI115718. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gerrity R. G. The role of the monocyte in atherogenesis: I. Transition of blood-borne monocytes into foam cells in fatty lesions. Am J Pathol. 1981 May;103(2):181–190. [PMC free article] [PubMed] [Google Scholar]
- Goldstein J. L., Ho Y. K., Basu S. K., Brown M. S. Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition. Proc Natl Acad Sci U S A. 1979 Jan;76(1):333–337. doi: 10.1073/pnas.76.1.333. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gown A. M., 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. [PMC free article] [PubMed] [Google Scholar]
- Hansson G. K., Hellstrand M., Rymo L., Rubbia L., Gabbiani G. Interferon gamma inhibits both proliferation and expression of differentiation-specific alpha-smooth muscle actin in arterial smooth muscle cells. J Exp Med. 1989 Nov 1;170(5):1595–1608. doi: 10.1084/jem.170.5.1595. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hodges R. S., Heaton R. J., Parker J. M., Molday L., Molday R. S. Antigen-antibody interaction. Synthetic peptides define linear antigenic determinants recognized by monoclonal antibodies directed to the cytoplasmic carboxyl terminus of rhodopsin. J Biol Chem. 1988 Aug 25;263(24):11768–11775. [PubMed] [Google Scholar]
- Inaba T., Yamada N., Gotoda T., Shimano H., Shimada M., Momomura K., Kadowaki T., Motoyoshi K., Tsukada T., Morisaki N. Expression of M-CSF receptor encoded by c-fms on smooth muscle cells derived from arteriosclerotic lesion. J Biol Chem. 1992 Mar 15;267(8):5693–5699. [PubMed] [Google Scholar]
- Jaakkola O., Nikkari T. Lipoprotein degradation and cholesterol esterification in primary cell cultures of rabbit atherosclerotic lesions. Am J Pathol. 1990 Aug;137(2):457–465. [PMC free article] [PubMed] [Google Scholar]
- Jonasson L., Holm J., Skalli O., Bondjers G., Hansson G. K. Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis. 1986 Mar-Apr;6(2):131–138. doi: 10.1161/01.atv.6.2.131. [DOI] [PubMed] [Google Scholar]
- Jonasson L., Holm J., Skalli O., Gabbiani G., Hansson G. K. Expression of class II transplantation antigen on vascular smooth muscle cells in human atherosclerosis. J Clin Invest. 1985 Jul;76(1):125–131. doi: 10.1172/JCI111934. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kocher O., Gabbiani G. Analysis of alpha-smooth-muscle actin mRNA expression in rat aortic smooth-muscle cells using a specific cDNA probe. Differentiation. 1987;34(3):201–209. doi: 10.1111/j.1432-0436.1987.tb00067.x. [DOI] [PubMed] [Google Scholar]
- 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. doi: 10.1038/343531a0. [DOI] [PubMed] [Google Scholar]
- Kraemer F. B., Tavangar K., Gandjei R. K., Kirlew K., Behr S. R. Effects of activation on lipid and lipoprotein metabolism in murine macrophages. Arteriosclerosis. 1990 Jan-Feb;10(1):8–16. doi: 10.1161/01.atv.10.1.8. [DOI] [PubMed] [Google Scholar]
- Krieger M. Complementation of mutations in the LDL pathway of receptor-mediated endocytosis by cocultivation of LDL receptor-defective hamster cell mutants. Cell. 1983 Jun;33(2):413–422. doi: 10.1016/0092-8674(83)90423-3. [DOI] [PubMed] [Google Scholar]
- Lamaziere J. M., Desmouliere A., Pascal M., Larrue J. Detection of atherosclerotic plaque with two monoclonal antibodies. 2P1A2 monoclonal antibody is specific for smooth muscle cells in atherosclerotic plaque. Atherosclerosis. 1988 Nov;74(1-2):115–126. doi: 10.1016/0021-9150(88)90198-0. [DOI] [PubMed] [Google Scholar]
- Li H., Cybulsky M. I., Gimbrone M. A., Jr, Libby P. An atherogenic diet rapidly induces VCAM-1, a cytokine-regulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endothelium. Arterioscler Thromb. 1993 Feb;13(2):197–204. doi: 10.1161/01.atv.13.2.197. [DOI] [PubMed] [Google Scholar]
- Li H., Cybulsky M. I., Gimbrone M. A., Jr, Libby P. Inducible expression of vascular cell adhesion molecule-1 by vascular smooth muscle cells in vitro and within rabbit atheroma. Am J Pathol. 1993 Dec;143(6):1551–1559. [PMC free article] [PubMed] [Google Scholar]
- Libby P., Hansson G. K. Involvement of the immune system in human atherogenesis: current knowledge and unanswered questions. Lab Invest. 1991 Jan;64(1):5–15. [PubMed] [Google Scholar]
- Libby P., O'Brien K. V. Culture of quiescent arterial smooth muscle cells in a defined serum-free medium. J Cell Physiol. 1983 May;115(2):217–223. doi: 10.1002/jcp.1041150217. [DOI] [PubMed] [Google Scholar]
- Luoma J., Hiltunen T., Särkioja T., Moestrup S. K., Gliemann J., Kodama T., Nikkari T., Ylä-Herttuala S. Expression of alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein and scavenger receptor in human atherosclerotic lesions. J Clin Invest. 1994 May;93(5):2014–2021. doi: 10.1172/JCI117195. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Matsumoto A., Naito M., Itakura H., Ikemoto S., Asaoka H., Hayakawa I., Kanamori H., Aburatani H., Takaku F., Suzuki H. 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. doi: 10.1073/pnas.87.23.9133. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Montalescot G., Faraggi M., Drobinski G., Messian O., Evans J., Grosgogeat Y., Thomas D. Myocardial viability in patients with Q wave myocardial infarction and no residual ischemia. Circulation. 1992 Jul;86(1):47–55. doi: 10.1161/01.cir.86.1.47. [DOI] [PubMed] [Google Scholar]
- Mosse P. R., Campbell G. R., Campbell J. H. Smooth muscle phenotypic expression in human carotid arteries. II. Atherosclerosis-free diffuse intimal thickenings compared with the media. Arteriosclerosis. 1986 Nov-Dec;6(6):664–669. doi: 10.1161/01.atv.6.6.664. [DOI] [PubMed] [Google Scholar]
- 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. [PMC free article] [PubMed] [Google Scholar]
- Pitas R. E. Expression of the acetyl low density lipoprotein receptor by rabbit fibroblasts and smooth muscle cells. Up-regulation by phorbol esters. J Biol Chem. 1990 Jul 25;265(21):12722–12727. [PubMed] [Google Scholar]
- Pitas R. E., Friera A., McGuire J., Dejager S. Further characterization of the acetyl LDL (scavenger) receptor expressed by rabbit smooth muscle cells and fibroblasts. Arterioscler Thromb. 1992 Nov;12(11):1235–1244. doi: 10.1161/01.atv.12.11.1235. [DOI] [PubMed] [Google Scholar]
- Pitas R. E., Innerarity T. L., Mahley R. W. Foam cells in explants of atherosclerotic rabbit aortas have receptors for beta-very low density lipoproteins and modified low density lipoproteins. Arteriosclerosis. 1983 Jan-Feb;3(1):2–12. doi: 10.1161/01.atv.3.1.2. [DOI] [PubMed] [Google Scholar]
- Rohrer L., Freeman M., Kodama T., Penman M., Krieger M. Coiled-coil fibrous domains mediate ligand binding by macrophage scavenger receptor type II. Nature. 1990 Feb 8;343(6258):570–572. doi: 10.1038/343570a0. [DOI] [PubMed] [Google Scholar]
- Schaffner T., Taylor K., Bartucci E. J., Fischer-Dzoga K., Beeson J. H., Glagov S., Wissler R. W. Arterial foam cells with distinctive immunomorphologic and histochemical features of macrophages. Am J Pathol. 1980 Jul;100(1):57–80. [PMC free article] [PubMed] [Google Scholar]
- Tanaka H., Sukhova G. K., Swanson S. J., Clinton S. K., Ganz P., Cybulsky M. I., Libby P. Sustained activation of vascular cells and leukocytes in the rabbit aorta after balloon injury. Circulation. 1993 Oct;88(4 Pt 1):1788–1803. doi: 10.1161/01.cir.88.4.1788. [DOI] [PubMed] [Google Scholar]
- Tsukada T., Rosenfeld M., Ross R., Gown A. M. Immunocytochemical analysis of cellular components in atherosclerotic lesions. Use of monoclonal antibodies with the Watanabe and fat-fed rabbit. Arteriosclerosis. 1986 Nov-Dec;6(6):601–613. doi: 10.1161/01.atv.6.6.601. [DOI] [PubMed] [Google Scholar]
- Tsukada T., Tippens D., Gordon D., Ross R., Gown A. M. HHF35, a muscle-actin-specific monoclonal antibody. I. Immunocytochemical and biochemical characterization. Am J Pathol. 1987 Jan;126(1):51–60. [PMC free article] [PubMed] [Google Scholar]
- Warner S. J., Auger K. R., Libby P. Interleukin 1 induces interleukin 1. II. Recombinant human interleukin 1 induces interleukin 1 production by adult human vascular endothelial cells. J Immunol. 1987 Sep 15;139(6):1911–1917. [PubMed] [Google Scholar]
- Warner S. J., Friedman G. B., Libby P. Immune interferon inhibits proliferation and induces 2'-5'-oligoadenylate synthetase gene expression in human vascular smooth muscle cells. J Clin Invest. 1989 Apr;83(4):1174–1182. doi: 10.1172/JCI113998. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ylä-Herttuala S., Rosenfeld M. E., Parthasarathy S., Sigal E., Särkioja T., Witztum J. L., 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. doi: 10.1172/JCI115111. [DOI] [PMC free article] [PubMed] [Google Scholar]