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Proc Natl Acad Sci U S A. Jan 17, 1995; 92(2): 402–406.
PMCID: PMC42748

Macrophage foam cells from experimental atheroma constitutively produce matrix-degrading proteinases.

Abstract

Monocyte-derived foam cells figure prominently in rupture-prone regions of atherosclerotic plaques. Peripheral blood monocytes in culture can produce certain enzymes that degrade extracellular matrix, known as matrix metalloproteinases (MMPs). Lipid-laden macrophages may thus contribute to weakening of extracellular matrix of rupture-prone atherosclerotic plaques. However, the spectrum and regulation of MMP production by foam cells remain unknown. To investigate this issue, we isolated lipid-laden macrophages from rabbit aortic lesions produced by a combination of hypercholesterolemia and balloon injury. Freshly isolated aortic macrophage foam cells, identified using cell-specific antibodies, contained immunoreactive stromelysin and interstitial collagenase, whereas alveolar macrophages isolated from the lungs of same rabbits did not. Macrophages from both tissue sources released gelatinolytic activity consistent with the 92-kDa gelatinase. In vitro, lipid-laden aortic macrophages, but not alveolar macrophages, synthesized de novo and released immunoprecipitable stromelysin and collagenase, with or without stimulation by phorbol ester or bacterial lipopolysaccharide. These stimuli caused foam cells to release additional gelatinolytic activity that migrated faster than a purified preparation of 92-kDa gelatinase in substrate-containing polyacrylamide gels, indicating activation of the 92-kDa gelatinase or induction of the 72-kDa gelatinase. Our results show that lipid-laden macrophages elaborate MMPs capable of degrading the major constituents of vascular extracellular matrix even without further stimulation. Therefore, these cells may contribute to remodeling of the extracellular matrix during atherogenesis and to the disruption of plaques often responsible for acute clinical manifestations of atherosclerosis.

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  • Lendon CL, Davies MJ, Born GV, Richardson PD. Atherosclerotic plaque caps are locally weakened when macrophages density is increased. Atherosclerosis. 1991 Mar;87(1):87–90. [PubMed]
  • Loree HM, Kamm RD, Stringfellow RG, Lee RT. Effects of fibrous cap thickness on peak circumferential stress in model atherosclerotic vessels. Circ Res. 1992 Oct;71(4):850–858. [PubMed]
  • van der Wal AC, Becker AE, van der Loos CM, Das PK. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation. 1994 Jan;89(1):36–44. [PubMed]
  • Aqel NM, Ball RY, Waldmann H, Mitchinson MJ. Identification of macrophages and smooth muscle cells in human atherosclerosis using monoclonal antibodies. J Pathol. 1985 Jul;146(3):197–204. [PubMed]
  • Klurfeld DM. Identification of foam cells in human atherosclerotic lesions as macrophages using monoclonal antibodies. Arch Pathol Lab Med. 1985 May;109(5):445–449. [PubMed]
  • Jonasson L, Holm J, Skalli O, Bondjers G, Hansson GK. Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis. 1986 Mar-Apr;6(2):131–138. [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. [PMC free article] [PubMed]
  • Werb Z, Banda MJ, Jones PA. Degradation of connective tissue matrices by macrophages. I. Proteolysis of elastin, glycoproteins, and collagen by proteinases isolated from macrophages. J Exp Med. 1980 Nov 1;152(5):1340–1357. [PMC free article] [PubMed]
  • Welgus HG, Campbell EJ, Cury JD, Eisen AZ, Senior RM, Wilhelm SM, Goldberg GI. Neutral metalloproteinases produced by human mononuclear phagocytes. Enzyme profile, regulation, and expression during cellular development. J Clin Invest. 1990 Nov;86(5):1496–1502. [PMC free article] [PubMed]
  • Campbell EJ, Cury JD, Shapiro SD, Goldberg GI, Welgus HG. Neutral proteinases of human mononuclear phagocytes. Cellular differentiation markedly alters cell phenotype for serine proteinases, metalloproteinases, and tissue inhibitor of metalloproteinases. J Immunol. 1991 Feb 15;146(4):1286–1293. [PubMed]
  • Fowler S. Characterization of foam cells in experimental atherosclerosis. Acta Med Scand Suppl. 1980;642:151–158. [PubMed]
  • Rosenfeld ME, Khoo JC, Miller E, Parthasarathy S, Palinski W, Witztum JL. Macrophage-derived foam cells freshly isolated from rabbit atherosclerotic lesions degrade modified lipoproteins, promote oxidation of low-density lipoproteins, and contain oxidation-specific lipid-protein adducts. J Clin Invest. 1991 Jan;87(1):90–99. [PMC free article] [PubMed]
  • Henney AM, Wakeley PR, Davies MJ, Foster K, Hembry R, Murphy G, Humphries S. Localization of stromelysin gene expression in atherosclerotic plaques by in situ hybridization. Proc Natl Acad Sci U S A. 1991 Sep 15;88(18):8154–8158. [PMC free article] [PubMed]
  • Minick CR, Stemerman MB, Insull W., Jr Role of endothelium and hypercholesterolemia in intimal thickening and lipid accumulation. Am J Pathol. 1979 Apr;95(1):131–158. [PMC free article] [PubMed]
  • Brinckerhoff CE, Suzuki K, Mitchell TI, Oram F, Coon CI, Palmiter RD, Nagase H. Rabbit procollagenase synthesized and secreted by a high-yield mammalian expression vector requires stromelysin (matrix metalloproteinase-3) for maximal activation. J Biol Chem. 1990 Dec 25;265(36):22262–22269. [PubMed]
  • Haley NJ, Shio H, Fowler S. Characterization of lipid-laden aortic cells from cholesterol-fed rabbits. I. Resolution of aortic cell populations by metrizamide density gradient centrifugation. Lab Invest. 1977 Sep;37(3):287–296. [PubMed]
  • Berberian PA, Jenison MW, Roddick V. Arterial prostaglandins and lysosomal function during atherogenesis. II. Isolated cells of diet-induced atherosclerotic aortas of rabbit. Exp Mol Pathol. 1985 Aug;43(1):36–55. [PubMed]
  • Galis ZS, Muszynski M, Sukhova GK, Simon-Morrissey E, Unemori EN, Lark MW, Amento E, Libby P. Cytokine-stimulated human vascular smooth muscle cells synthesize a complement of enzymes required for extracellular matrix digestion. Circ Res. 1994 Jul;75(1):181–189. [PubMed]
  • Murphy G, Reynolds JJ, Werb Z. Biosynthesis of tissue inhibitor of metalloproteinases by human fibroblasts in culture. Stimulation by 12-O-tetradecanoylphorbol 13-acetate and interleukin 1 in parallel with collagenase. J Biol Chem. 1985 Mar 10;260(5):3079–3083. [PubMed]
  • Wilhelm SM, Eisen AZ, Teter M, Clark SD, Kronberger A, Goldberg G. Human fibroblast collagenase: glycosylation and tissue-specific levels of enzyme synthesis. Proc Natl Acad Sci U S A. 1986 Jun;83(11):3756–3760. [PMC free article] [PubMed]
  • Galis ZS, Sukhova GK, Lark MW, Libby P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest. 1994 Dec;94(6):2493–2503. [PMC free article] [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. [PMC free article] [PubMed]
  • Hansson GK, Seifert PS, Olsson G, Bondjers G. Immunohistochemical detection of macrophages and T lymphocytes in atherosclerotic lesions of cholesterol-fed rabbits. Arterioscler Thromb. 1991 May-Jun;11(3):745–750. [PubMed]
  • Hansson GK, Jonasson L, Holm J, Clowes MM, Clowes AW. Gamma-interferon regulates vascular smooth muscle proliferation and Ia antigen expression in vivo and in vitro. Circ Res. 1988 Oct;63(4):712–719. [PubMed]
  • Warner SJ, Friedman GB, 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. [PMC free article] [PubMed]
  • Amento EP, Ehsani N, Palmer H, Libby P. Cytokines and growth factors positively and negatively regulate interstitial collagen gene expression in human vascular smooth muscle cells. Arterioscler Thromb. 1991 Sep-Oct;11(5):1223–1230. [PubMed]
  • Ylä-Herttuala S, Palinski W, Rosenfeld ME, Parthasarathy S, Carew TE, Butler S, Witztum JL, Steinberg D. Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man. J Clin Invest. 1989 Oct;84(4):1086–1095. [PMC free article] [PubMed]
  • Haberland ME, Fong D, Cheng L. Malondialdehyde-altered protein occurs in atheroma of Watanabe heritable hyperlipidemic rabbits. Science. 1988 Jul 8;241(4862):215–218. [PubMed]
  • Barath P, Fishbein MC, Cao J, Berenson J, Helfant RH, Forrester JS. Detection and localization of tumor necrosis factor in human atheroma. Am J Cardiol. 1990 Feb 1;65(5):297–302. [PubMed]
  • Clinton SK, Fleet JC, Loppnow H, Salomon RN, Clark BD, Cannon JG, Shaw AR, Dinarello CA, Libby P. Interleukin-1 gene expression in rabbit vascular tissue in vivo. Am J Pathol. 1991 Apr;138(4):1005–1014. [PMC free article] [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. [PMC free article] [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. [PMC free article] [PubMed]
  • Richardson PD, Davies MJ, Born GV. Influence of plaque configuration and stress distribution on fissuring of coronary atherosclerotic plaques. Lancet. 1989 Oct 21;2(8669):941–944. [PubMed]
  • Cheng GC, Loree HM, Kamm RD, Fishbein MC, Lee RT. Distribution of circumferential stress in ruptured and stable atherosclerotic lesions. A structural analysis with histopathological correlation. Circulation. 1993 Apr;87(4):1179–1187. [PubMed]
  • Ross R, Klebanoff SJ. The smooth muscle cell. I. In vivo synthesis of connective tissue proteins. J Cell Biol. 1971 Jul;50(1):159–171. [PMC free article] [PubMed]
  • Stary HC, Blankenhorn DH, Chandler AB, Glagov S, Insull W, Jr, Richardson M, Rosenfeld ME, Schaffer SA, Schwartz CJ, Wagner WD, et al. A definition of the intima of human arteries and of its atherosclerosis-prone regions. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation. 1992 Jan;85(1):391–405. [PubMed]

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