Abstract
Intimal cell death has been a recognized feature of advanced atherosclerotic disease. With the advent of DNA in situ end labelling and/or ultrastructural techniques, recent findings suggest that cells of an atheroma undergo programmed cell death or apoptosis. The pathophysiologic relevance of apoptosis in atherosclerotic disease is debatable. Apoptotic cell death may influence lesion progression and thus reduce overall plaque burden. Alternatively, apoptosis may prove a means of quenching the inflammation, converting cellular-rich lesions to so-called ‘stable’ fibrous hypocellular plaques or conversely weaken the fibrous cap causing plaque rupture, a major cause of acute coronary syndromes. Apoptotic cells within plaques are typically macrophages, smooth muscle cells and T-cells and the frequency of death varies in the different regions of the lesion. The precise signalling pathways of apoptosis in plaques are unknown. There is however, some evidence that production of immune cytokines may promote apoptosis through activation of the Fas ligand-mediated death pathway. Genetic signals that regulate apoptosis in the atheroma, at least in smooth muscle cells, may involve the tumour suppressor genes p105 RB and p53. Further studies as to the relevance of apoptosis in acute coronary syndromes and potential mechanisms are emerging.
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References
Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993; 362: 801-809.
Davies MJ, Woolf N. Atherosclerosis: what is it and why does it occur? Br Heart J 1993; 69: S3-S11.
Gordon D, Reidy MA, Benditt EP, Schwartz SM. Cell proliferation in human coronary arteries. Proc Natl Acad Sci USA 1990; 87: 4600-4604.
Virchow R. Der ateromatose prozess der arterien. Wein Med Wochenschr 1856; 6: 825.
Lee RT, Libby P. The unstable atheroma. Arterioscler Thromb Vasc Biol 1997; 17: 1859-1867.
Davies MJ, Thomas AC. Plaque fissuring—the cause of acute myocardial infarction, sudden ischaemic death, and crescendo angina. Br Heart J 1985; 53: 363-373.
Wijsman JH, Jonker RR, Keijzer R, van de Velde CJ, Cornelisse CJ, van Dierendonck JH. A new method to detect apoptosis in paraffin sections: in situ end-labelling of fragmented DNA. J Histochem Cytochem 1993; 41: 7-12.
Gavrieli Y, Sherman Y, Ben-Sasson SA. Identification of programmed cell death in situ via specific labelling of nuclear DNA fragmentation. J Cell Biol 1992; 119: 493-501.
Trump BF, Berezesky IK, Chang SH, Phelps PC. The pathways of cell death: oncosis, apoptosis, and necrosis. Toxicol Pathol 1997; 25: 82-88.
Bjorkerud S, Bjorkerud B. Apoptosis is abundant in human atherosclerotic lesions, especially in inflammatory cells (macrophages and T cells), and may contribute to the accumulation of gruel and plaque instability. Am J Pathol 1996; 149: 367-380.
Kockx MM, Muhring J, Knaapen MW, de Meyer GR. RNA synthesis and splicing interferes with DNA in situ end labelling techniques used to detect apoptosis. Am J Pathol 1998; 152: 885-888.
Geng YJ, Libby P. Evidence for apoptosis in advanced human atheroma. Colocalization with interleukin-1 beta-converting enzyme. Am J Pathol 1995; 147: 251-266.
Han DK, Haudenschild CC, Hong MK, Tinkle BT, Leon MB, Liau G. Evidence for apoptosis in human atherogenesis and in a rat vascular injury model. Am J Pathol 1995; 147: 267-277.
Isner JM, Kearney M, Bortman S, Passeri J. Apoptosis in human atherosclerosis and restenosis [see comments]. Circulation 1995; 91: 2703-2711.
Mallat Z, Ohan J, Leseche G, Tedgui A. Colocalization of CPP-32 with apoptotic cells in human atherosclerotic plaques. Circulation 1997; 96: 424-428.
Geng YJ, Henderson LE, Levesque EB, Muszynski M, Libby P. Fas is expressed in human atherosclerotic intima and promotes apoptosis of cytokine-primed human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 1997; 17: 2200-2208.
Crisby M, Kallin B, Thyberg J, et al. Cell death in human atherosclerotic plaques involves both oncosis and apoptosis. Atherosclerosis 1997; 130: 17-27.
Jovinge S, Crisby M, Thyberg J, Nilsson J. DNA fragmentation and ultrastructural changes of degenerating cells in atherosclerotic lesions and smooth muscle cells exposed to oxidized LDL in vitro. Arterioscler Thromb Vasc Biol 1997; 17: 2225-2231.
Kockx MM, De Meyer GR, Muhring J, Jacob W, Bult H, Herman AG. Apoptosis and related proteins in different stages of human atherosclerotic plaques. Circulation 1998; 97: 2307-2315.
Cai W, Devaux B, Schaper W, Schaper J. The role of Fas/APO 1 and apoptosis in the development of human atherosclerotic lesions. Atherosclerosis 1997; 131: 177-186.
Natural history of aortic and coronary atherosclerotic lesions in. Arterioscler Thromb 1993; 13: 1291-1298.
Strong JP, Malcom GT, Oalmann MC, Wissler RW. The PDAY Study: natural history, risk factors, and pathobiology. Ann N Y Acad Sci 1997; 811: 226-235.
Libby P, Sukhova G, Lee RT, Galis ZS. Cytokines regulate vascular functions related to stability of the atherosclerotic plaque. J Cardiovasc Pharmacol 1995; 25(Suppl 2): S9-S12.
Sumimoto S, Ishigami T, Horiguchi Y, et al. Anti-Fas antibody induces different types of cell death in the human histiocytic cell line, U937, and the human B cell line, B104: the role of single-strand DNA breaks and poly (ADP-ribosyl)ation in cell death. Cell Immunol 1994; 153: 184-193.
Fukuo K, Suhara T, Nakahashi T, et al. Activated T cells induce up-regulation of Fas antigen in cultured endothelial cells. Heart Vessels 1997; (Suppl 12): 81-83.
Maciejewski J, Selleri C, Anderson S, Young NS. Fas antigen expression on CD34+ human marrow cells is induced by interferon gamma and tumor necrosis factor alpha and potentiates cytokine-mediated hematopoietic suppression in vitro. Blood 1995; 85: 3183-3190.
Fraser A, Evan G. A license to kill. Cell 1996; 85: 781-784.
Weller M, Frei K, Groscurth P, Krammer PH, Yonekawa Y, Fontana A. Anti-Fas/APO-1 antibody-mediated apoptosis of cultured human glioma cells. Induction and modulation of sensitivity by cytokines. J Clin Invest 1994; 94: 954-964.
Fukuo K, Nakahashi T, Nomura S, et al. Possible participation of Fas-mediated apoptosis in the mechanism of atherosclerosis. Gerontology 1997; 43(Suppl 1): 35-42.
Um HD, Orenstein JM, Wahl SM. Fas mediates apoptosis in human monocytes by a reactive oxygen intermediate dependent pathway. J Immunol 1996; 156: 3469-3477.
Yang X, Galeano NF, Szabolcs M, Sciacca RR, Cannon PJ. Oxidized low density lipoproteins alter macrophage lipid uptake, apoptosis, viability and nitric oxide synthesis. J Nutr 1996; 126: 1072S-1075S.
Nishio E, Arimura S, Watanabe Y. Oxidized LDL induces apoptosis in cultured smooth muscle cells: a possible role for 7-ketocholesterol. Biochem Biophys Res Commun 1996; 223: 413-418.
Li W, Yuan XM, Olsson AG, Brunk UT. Uptake of oxidized LDL by macrophages results in partial lysosomal enzyme inactivation and relocation. Arterioscler Thromb Vasc Biol 1998; 18: 177-184.
Li PF, Dietz R, von Harsdorf R. Differential effect of hydrogen peroxide and superoxide anion on apoptosis and proliferation of vascular smooth muscle cells. Circulation 1997; 96: 3602-3609.
Li PF, Dietz R, von Harsdorf R. Reactive oxygen species induce apoptosis of vascular smooth muscle cell. FEBS Lett 1997; 404: 249-252.
Allsopp TE, Wyatt S, Paterson HF, Davies AM. The proto-oncogene bcl-2 can selectively rescue neurotrophic factor-dependent neurons from apoptosis. Cell 1993; 73: 295-307.
Bennett MR, Evan GI, Schwartz SM. Apoptosis of human vascular smooth muscle cells derived from normal vessels and coronary atherosclerotic plaques. J Clin Invest 1995; 95: 2266-2274.
White E. Life, death, and the pursuit of apoptosis. Genes Dev 1996; 10: 1-15.
Cory S. Regulation of lymphocyte survival by the bcl-2 gene family. Annu Rev Immunol 1995; 13: 513-543.
Van Der Vliet HJ, Wever PC, Van Diepen FN, Yong SL, Ten Berge IJ. Quantification of Bax/Bcl-2 ratios in peripheral blood lymphocytes, monocytes and granulocytes and their relation to susceptibility to anti-Fas (anti-CD95)-induced apoptosis. Clin Exp Immunol 1997; 110: 324-328.
Hockenbery DM, Oltvai ZN, Yin XM, Milliman CL, Korsmeyer SJ. Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell 1993; 75: 241-251.
Berliner JA, Navab M, Fogelman AM, et al. Atherosclerosis: basic mechanisms. Oxidation, inflammation, and genetics. Circulation 1995; 91: 2488-2496.
Bennett MR, Littlewood TD, Schwartz SM, Weissberg PL. Increased sensitivity of human vascular smooth muscle cells from atherosclerotic plaques to p53-mediated apoptosis. Circ Res 1997; 81: 591-599.
Bennett MR, Macdonald K, Chan SW, Boyle JJ, Weissberg PL. Cooperative interactions between RB and p53 regulate cell proliferation, cell senescence, and apoptosis in human vascular smooth muscle cells from atherosclerotic plaques. Circ Res 1998; 82: 704-712.
Kolodgie FD, Narula J, Burke AP, et al. Association of atherosclerotic plaque rupture in sudden coronary death with extensive focal apoptosis of macrophages [Abstract]. Circulation 1998; 98: I-47.
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Kolodgie, F.D., Narula, J., Guillo, P. et al. Apoptosis in human atherosclerotic plaques. Apoptosis 4, 5–10 (1999). https://doi.org/10.1023/A:1009645730270
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DOI: https://doi.org/10.1023/A:1009645730270