This Article Order Full text via Infotrieve Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bjorkerud, S. Articles by Bjorkerud, B. Search for Related Content PubMed PubMed Citation Articles by Bjorkerud, S. Articles by Bjorkerud, B.

American Journal of Pathology, Vol 149, 367-380, Copyright © 1996 by American Society for Investigative Pathology

REGULAR ARTICLES

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

S Bjorkerud and B Bjorkerud
Department of Pathology, Goteborg University, Sahlgrenska University Hospital, Sweden.

Death of intimal tissue may lead to plaque rupture with thrombosis, which is the basis of the most severe clinical consequences of atherosclerosis. Little is known about the mechanisms that promote intimal cell death or its nature. This work was undertaken to elucidate the extent to which, the cell types in which, and where programmed cell death, apoptosis, might occur in atherosclerotic lesions. The material was fibrous or fibro-fatty non-ulcerated lesions from the human thoracic aorta and coronary arteries. Apoptosis was indicated by the in situ labeling of internucleosomally degraded DNA with the TUNEL technique, which has a preference for apoptosis as compared with cell necrosis and was combined with the immunohistochemical typing of cells. Apoptosis was corroborated by morphological criteria on the light and electron microscope levels and by the presence of an apoptosis-specific protein. It was common in the lesions and virtually absent in non- atherosclerotic regions. It occurred in smooth muscle cells subendothelially, in places of the fibrous cap, and in the underlying media, which may destabilize the plaque and promote rupture. Inflammatory cells, ie, macrophages and T cells, appeared abundantly subendothelially, in the fibrous cap, and in the shoulder regions, and apoptosis was common, maybe reflecting a means for quenching of the inflammatory reaction. Many macrophages contained abundant apoptotic material indicative of phagocytosis of apoptotic cells, but the occurrence of apoptosis, even in some of these cells, and of apoptotic material extracellularly and the very high numbers of apoptotic cells that were encountered may indicate insufficient mechanisms for the removal of apoptotic cells in the atherosclerotic lesion. It is not possible to decide as yet whether this is due to overloading with cellular material by inflammation and cell multiplication, to an increased frequency of apoptosis, to a reduction of the removal/degradation of apoptotic material by macrophages, or a combination of these factors.

This article has been cited by other articles:

				H. Fujimoto, J.-i. Taguchi, Y. Imai, S. Ayabe, H. Hashimoto, H. Kobayashi, K. Ogasawara, T. Aizawa, M. Yamakado, R. Nagai, et al. Manganese superoxide dismutase polymorphism affects the oxidized low-density lipoprotein-induced apoptosis of macrophages and coronary artery disease Eur. Heart J., May 2, 2008; 29(10): 1267 - 1274. [Abstract] [Full Text] [PDF]

				M. Sarai, D. Hartung, A. Petrov, J. Zhou, N. Narula, L. Hofstra, F. Kolodgie, S. Isobe, S. Fujimoto, J.-L. Vanderheyden, et al. Broad and Specific Caspase Inhibitor-Induced Acute Repression of Apoptosis in Atherosclerotic Lesions Evaluated by Radiolabeled Annexin A5 Imaging J. Am. Coll. Cardiol., December 11, 2007; 50(24): 2305 - 2312. [Abstract] [Full Text] [PDF]

				N. Tentolouris, R. Nzietchueng, V. Cattan, G. Poitevin, P. Lacolley, A. Papazafiropoulou, D. Perrea, N. Katsilambros, and A. Benetos White Blood Cells Telomere Length Is Shorter in Males With Type 2 Diabetes and Microalbuminuria Diabetes Care, November 1, 2007; 30(11): 2909 - 2915. [Abstract] [Full Text] [PDF]

				M. Myoishi, H. Hao, T. Minamino, K. Watanabe, K. Nishihira, K. Hatakeyama, Y. Asada, K.-i. Okada, H. Ishibashi-Ueda, G. Gabbiani, et al. Increased Endoplasmic Reticulum Stress in Atherosclerotic Plaques Associated With Acute Coronary Syndrome Circulation, September 11, 2007; 116(11): 1226 - 1233. [Abstract] [Full Text] [PDF]

				O. P. Blanc-Brude, E. Teissier, Y. Castier, G. Leseche, A.-P. Bijnens, M. Daemen, B. Staels, Z. Mallat, and A. Tedgui IAP Survivin Regulates Atherosclerotic Macrophage Survival Arterioscler. Thromb. Vasc. Biol., April 1, 2007; 27(4): 901 - 907. [Abstract] [Full Text] [PDF]

				V. Croons, W. Martinet, A. G. Herman, J.-P. Timmermans, and G. R. Y. De Meyer Selective Clearance of Macrophages in Atherosclerotic Plaques by the Protein Synthesis Inhibitor Cycloheximide J. Pharmacol. Exp. Ther., March 1, 2007; 320(3): 986 - 993. [Abstract] [Full Text] [PDF]

				D. M. Schrijvers, G. R.Y. De Meyer, A. G. Herman, and W. Martinet Phagocytosis in atherosclerosis: Molecular mechanisms and implications for plaque progression and stability Cardiovasc Res, February 1, 2007; 73(3): 470 - 480. [Abstract] [Full Text] [PDF]

				V. K. Bhatia, S. Yun, V. Leung, D. C. Grimsditch, G. M. Benson, M. B. Botto, J. J. Boyle, and D. O. Haskard Complement C1q Reduces Early Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice Am. J. Pathol., January 1, 2007; 170(1): 416 - 426. [Abstract] [Full Text] [PDF]

				W. Li, M. Ostblom, L.-H. Xu, A. Hellsten, P. Leanderson, B. Liedberg, U. T. Brunk, J. W. Eaton, and X.-M. Yuan Cytocidal effects of atheromatous plaque components: the death zone revisited FASEB J, November 1, 2006; 20(13): 2281 - 2290. [Abstract] [Full Text] [PDF]

				X. Houard, A. Leclercq, V. Fontaine, M. Coutard, J.-L. Martin-Ventura, B. Ho-Tin-Noe, Z. Touat, O. Meilhac, and J.-B. Michel Retention and Activation of Blood-Borne Proteases in the Arterial Wall: Implications for Atherothrombosis J. Am. Coll. Cardiol., October 27, 2006; 48(9_Suppl_A): A3 - A9. [Abstract] [Full Text] [PDF]

				S. Isobe, S. Tsimikas, J. Zhou, S. Fujimoto, M. Sarai, M. J. Branks, A. Fujimoto, L. Hofstra, C. P. Reutelingsperger, T. Murohara, et al. Noninvasive Imaging of Atherosclerotic Lesions in Apolipoprotein E-Deficient and Low-Density-Lipoprotein Receptor-Deficient Mice with Annexin A5 J. Nucl. Med., September 1, 2006; 47(9): 1497 - 1505. [Abstract] [Full Text] [PDF]

				T. Kumamoto, Y. Kawai, K. Arakawa, N. Morikawa, J. Kuribara, H. Tada, K. Taniguchi, R. Tatami, I. Miyamori, Y. Kominato, et al. Association of Gln222Arg polymorphism in the deoxyribonuclease I (DNase I) gene with myocardial infarction in Japanese patients Eur. Heart J., September 1, 2006; 27(17): 2081 - 2087. [Abstract] [Full Text] [PDF]

				B.-A. Khaw, Y. Tekabe, and L. L. Johnson Imaging Experimental Atherosclerotic Lesions in ApoE Knockout Mice: Enhanced Targeting with Z2D3-Anti-DTPA Bispecific Antibody and 99mTc-Labeled Negatively Charged Polymers J. Nucl. Med., May 1, 2006; 47(5): 868 - 876. [Abstract] [Full Text] [PDF]

				J. Nigro, N. Osman, A. M. Dart, and P. J. Little Insulin Resistance and Atherosclerosis Endocr. Rev., May 1, 2006; 27(3): 242 - 259. [Abstract] [Full Text] [PDF]

				M. J. Sampson, M. S. Winterbone, J. C. Hughes, N. Dozio, and D. A. Hughes Monocyte Telomere Shortening and Oxidative DNA Damage in Type 2 Diabetes Diabetes Care, February 1, 2006; 29(2): 283 - 289. [Abstract] [Full Text] [PDF]

				K. Sato, A. Niessner, S. L. Kopecky, R. L. Frye, J. J. Goronzy, and C. M. Weyand TRAIL-expressing T cells induce apoptosis of vascular smooth muscle cells in the atherosclerotic plaque J. Exp. Med., January 23, 2006; 203(1): 239 - 250. [Abstract] [Full Text] [PDF]

				D. Hartung, M. Sarai, A. Petrov, F. Kolodgie, N. Narula, J. Verjans, R. Virmani, C. Reutelingsperger, L. Hofstra, and J. Narula Resolution of Apoptosis in Atherosclerotic Plaque by Dietary Modification and Statin Therapy J. Nucl. Med., December 1, 2005; 46(12): 2051 - 2056. [Abstract] [Full Text] [PDF]

				S G Baidya and Q-T Zeng Helper T cells and atherosclerosis: the cytokine web Postgrad. Med. J., December 1, 2005; 81(962): 746 - 752. [Abstract] [Full Text] [PDF]

				I. Tabas Consequences and Therapeutic Implications of Macrophage Apoptosis in Atherosclerosis: The Importance of Lesion Stage and Phagocytic Efficiency Arterioscler. Thromb. Vasc. Biol., November 1, 2005; 25(11): 2255 - 2264. [Abstract] [Full Text] [PDF]

				H. Ono, T. Ichiki, H. Ohtsubo, K. Fukuyama, I. Imayama, Y. Hashiguchi, J. Sadoshima, and K. Sunagawa Critical Role of Mst1 in Vascular Remodeling After Injury Arterioscler. Thromb. Vasc. Biol., September 1, 2005; 25(9): 1871 - 1876. [Abstract] [Full Text] [PDF]

				K. Yaraei, L. A. Campbell, X. Zhu, W. C. Liles, C.-c. Kuo, and M. E. Rosenfeld Chlamydia pneumoniae Augments the Oxidized Low-Density Lipoprotein-Induced Death of Mouse Macrophages by a Caspase-Independent Pathway Infect. Immun., July 1, 2005; 73(7): 4315 - 4322. [Abstract] [Full Text] [PDF]

				L. L. Johnson, L. Schofield, T. Donahay, N. Narula, and J. Narula 99mTc-Annexin V Imaging for In Vivo Detection of Atherosclerotic Lesions in Porcine Coronary Arteries J. Nucl. Med., July 1, 2005; 46(7): 1186 - 1193. [Abstract] [Full Text] [PDF]

				D. M. Schrijvers, G. R.Y. De Meyer, M. M. Kockx, A. G. Herman, and W. Martinet Phagocytosis of Apoptotic Cells by Macrophages Is Impaired in Atherosclerosis Arterioscler. Thromb. Vasc. Biol., June 1, 2005; 25(6): 1256 - 1261. [Abstract] [Full Text] [PDF]

				P. L. Weissberg Noninvasive Imaging of Atherosclerosis: The Biology Behind the Pictures J. Nucl. Med., November 1, 2004; 45(11): 1794 - 1795. [Full Text] [PDF]

				F. Blaschke, D. Bruemmer, F. Yin, Y. Takata, W. Wang, M. C. Fishbein, T. Okura, J. Higaki, K. Graf, E. Fleck, et al. C-Reactive Protein Induces Apoptosis in Human Coronary Vascular Smooth Muscle Cells Circulation, August 3, 2004; 110(5): 579 - 587. [Abstract] [Full Text] [PDF]

				K. A. Lindstedt, M. J. Leskinen, and P. T. Kovanen Proteolysis of the Pericellular Matrix: A Novel Element Determining Cell Survival and Death in the Pathogenesis of Plaque Erosion and Rupture Arterioscler. Thromb. Vasc. Biol., August 1, 2004; 24(8): 1350 - 1358. [Abstract] [Full Text] [PDF]

				J. L. Martin-Ventura, L. M. Blanco-Colio, B. Munoz-Garcia, A. Gomez-Hernandez, A. Arribas, L. Ortega, J. Tunon, and J. Egido NF-{kappa}B Activation and Fas Ligand Overexpression in Blood and Plaques of Patients With Carotid Atherosclerosis: Potential Implication in Plaque Instability Stroke, February 1, 2004; 35(2): 458 - 463. [Abstract] [Full Text] [PDF]

				F. D. Kolodgie, A. Petrov, R. Virmani, N. Narula, J. W. Verjans, D. K. Weber, D. Hartung, N. Steinmetz, J. L. Vanderheyden, M. A. Vannan, et al. Targeting of Apoptotic Macrophages and Experimental Atheroma With Radiolabeled Annexin V: A Technique With Potential for Noninvasive Imaging of Vulnerable Plaque Circulation, December 23, 2003; 108(25): 3134 - 3139. [Abstract] [Full Text] [PDF]

				P. Gargalovic and L. Dory Cellular apoptosis is associated with increased caveolin-1 expression in macrophages J. Lipid Res., September 1, 2003; 44(9): 1622 - 1632. [Abstract] [Full Text] [PDF]

				A. J. Merched, E. Williams, and L. Chan Macrophage-Specific p53 Expression Plays a Crucial Role in Atherosclerosis Development and Plaque Remodeling Arterioscler. Thromb. Vasc. Biol., September 1, 2003; 23(9): 1608 - 1614. [Abstract] [Full Text] [PDF]

				T. Q. Nhan, W. C. Liles, A. Chait, J. T. Fallon, and S. M. Schwartz The p17 Cleaved Form of Caspase-3 Is Present Within Viable Macrophages In Vitro and in Atherosclerotic Plaque Arterioscler. Thromb. Vasc. Biol., July 1, 2003; 23(7): 1276 - 1282. [Abstract] [Full Text] [PDF]

				M. Serradell, M. Diaz-Ricart, A. Cases, J. Petriz, A. Ordinas, and G. Escolar Uraemic medium accelerates proliferation but does not induce apoptosis of endothelial cells in culture Nephrol. Dial. Transplant., June 1, 2003; 18(6): 1079 - 1085. [Abstract] [Full Text] [PDF]

				C. Heeschen, S. Dimmeler, C. W. Hamm, S. Fichtlscherer, E. Boersma, M. L. Simoons, A. M. Zeiher, and for the CAPTURE Study Investigators Serum Level of the Antiinflammatory Cytokine Interleukin-10 Is an Important Prognostic Determinant in Patients With Acute Coronary Syndromes Circulation, April 29, 2003; 107(16): 2109 - 2114. [Abstract] [Full Text] [PDF]

				P. K. Shah Mechanisms of plaque vulnerability and rupture J. Am. Coll. Cardiol., February 19, 2003; 41(4_Suppl_S): 15S - 22S. [Abstract] [Full Text] [PDF]

				M. J. Leskinen, K. A. Lindstedt, Y. Wang, and P. T. Kovanen Mast Cell Chymase Induces Smooth Muscle Cell Apoptosis by a Mechanism Involving Fibronectin Degradation and Disruption of Focal Adhesions Arterioscler. Thromb. Vasc. Biol., February 1, 2003; 23(2): 238 - 243. [Abstract] [Full Text] [PDF]

				M. Zorc, R. Zorc-Pleskovic, O. Vraspir-Porenta, M. Legan, and D. Petrovic Apoptosis and Histopathologic Changes in Diffuse Coronary Atherosclerosis Angiology, January 1, 2003; 54(1): 81 - 84. [Abstract] [PDF]

				J. Herrmann, W. D. Edwards, D. R. Holmes Jr, K. L. Shogren, L. O. Lerman, A. Ciechanover, and A. Lerman Increased ubiquitin immunoreactivity in unstable atherosclerotic plaques associated with acute coronary syndromes J. Am. Coll. Cardiol., December 4, 2002; 40(11): 1919 - 1927. [Abstract] [Full Text] [PDF]

				D. Y. Li, H. J. Chen, E. D. Staples, K. Ozaki, B. Annex, B. K. Singh, R. Vermani, and J. L. Mehtat Oxidized Low-Density Lipoprotein Receptor LOX-1 and Apoptosis in Human Atherosclerotic Lesions Journal of Cardiovascular Pharmacology and Therapeutics, September 1, 2002; 7(3): 147 - 153. [Abstract] [PDF]

				Y.-J. Geng and P. Libby Progression of Atheroma: A Struggle Between Death and Procreation Arterioscler. Thromb. Vasc. Biol., September 1, 2002; 22(9): 1370 - 1380. [Abstract] [Full Text] [PDF]

				N. M. Ananyeva, D. V. Kouiavskaia, M. Shima, and E. L. Saenko Intrinsic pathway of blood coagulation contributes to thrombogenicity of atherosclerotic plaque Blood, May 29, 2002; 99(12): 4475 - 4485. [Abstract] [Full Text] [PDF]

				M. Bond, G. Murphy, M. R. Bennett, A. C. Newby, and A. H. Baker Tissue Inhibitor of Metalloproteinase-3 Induces a Fas-associated Death Domain-dependent Type II Apoptotic Pathway J. Biol. Chem., April 12, 2002; 277(16): 13787 - 13795. [Abstract] [Full Text] [PDF]

				E. Lorenzo, C. Ruiz-Ruiz, A. J. Quesada, G. Hernandez, A. Rodriguez, A. Lopez-Rivas, and J. M. Redondo Doxorubicin Induces Apoptosis and CD95 Gene Expression in Human Primary Endothelial Cells through a p53-dependent Mechanism J. Biol. Chem., March 22, 2002; 277(13): 10883 - 10892. [Abstract] [Full Text] [PDF]

				M. Masse, M.-J. Hebert, S. Troyanov, N. Vigneault, I. Sirois, and F. Madore Soluble Fas is a marker of peripheral arterial occlusive disease in haemodialysis patients Nephrol. Dial. Transplant., March 1, 2002; 17(3): 485 - 491. [Abstract] [Full Text] [PDF]

				K. T. Iida, H. Suzuki, H. Sone, H. Shimano, H. Toyoshima, S. Yatoh, T. Asano, Y. Okuda, and N. Yamada Insulin Inhibits Apoptosis of Macrophage Cell Line, THP-1 Cells, via Phosphatidylinositol-3-Kinase-Dependent Pathway Arterioscler. Thromb. Vasc. Biol., March 1, 2002; 22(3): 380 - 386. [Abstract] [Full Text] [PDF]

				A. Matsuda, Y. Suzuki, K. Kondo, Y. Ikeda, and K. Umemura Hypercholesterolemia induces regression in neointimal thickening due to apoptosis of vascular smooth muscle cells in the hamster endothelial injury model Cardiovasc Res, February 1, 2002; 53(2): 512 - 523. [Abstract] [Full Text] [PDF]

				T. Suhara, H.-S. Kim, L. A. Kirshenbaum, and K. Walsh Suppression of Akt Signaling Induces Fas Ligand Expression: Involvement of Caspase and Jun Kinase Activation in Akt-Mediated Fas Ligand Regulation Mol. Cell. Biol., January 15, 2002; 22(2): 680 - 691. [Abstract] [Full Text] [PDF]

				J. J. Boyle, D. E. Bowyer, P. L. Weissberg, and M. R. Bennett Human Blood-Derived Macrophages Induce Apoptosis in Human Plaque-Derived Vascular Smooth Muscle Cells by Fas-Ligand/Fas Interactions Arterioscler. Thromb. Vasc. Biol., September 1, 2001; 21(9): 1402 - 1407. [Abstract] [Full Text] [PDF]

				J.F. Bentzon and E. Falk Coronary plaques calling for action -- why, where and how many? Eur. Heart J. Suppl., August 1, 2001; 3(suppl_I): I3 - I9. [Abstract] [PDF]

				M. Leskinen, Y. Wang, D. Leszczynski, K. A. Lindstedt, and P. T. Kovanen Mast Cell Chymase Induces Apoptosis of Vascular Smooth Muscle Cells Arterioscler. Thromb. Vasc. Biol., April 1, 2001; 21(4): 516 - 522. [Abstract] [Full Text] [PDF]

				Y. Okura, M. Brink, H. Itabe, K. J. Scheidegger, A. Kalangos, and P. Delafontaine Oxidized Low-Density Lipoprotein Is Associated With Apoptosis of Vascular Smooth Muscle Cells in Human Atherosclerotic Plaques Circulation, November 28, 2000; 102(22): 2680 - 2686. [Abstract] [Full Text] [PDF]

				H. Obara, A. Takayanagi, J. Hirahashi, K. Tanaka, G. Wakabayashi, K. Matsumoto, M. Shimazu, N. Shimizu, and M. Kitajima Overexpression of Truncated I{kappa}B{alpha} Induces TNF-{alpha}-Dependent Apoptosis in Human Vascular Smooth Muscle Cells Arterioscler. Thromb. Vasc. Biol., October 1, 2000; 20(10): 2198 - 2204. [Abstract] [Full Text] [PDF]

				F. D. Kolodgie, J. Narula, A. P. Burke, N. Haider, A. Farb, Y. Hui-Liang, J. Smialek, and R. Virmani Localization of Apoptotic Macrophages at the Site of Plaque Rupture in Sudden Coronary Death Am. J. Pathol., October 1, 2000; 157(4): 1259 - 1268. [Abstract] [Full Text] [PDF]

				J. A. Hamilton, G. Whitty, and W. Jessup Oxidized LDL Can Promote Human Monocyte Survival Arterioscler. Thromb. Vasc. Biol., October 1, 2000; 20 (10): 2329 - 2331. [Full Text] [PDF]

				K. Walsh, R. C. Smith, and H.-S. Kim Vascular Cell Apoptosis in Remodeling, Restenosis, and Plaque Rupture Circ. Res., August 4, 2000; 87(3): 184 - 188. [Full Text] [PDF]

				A. Fischer, D. E Gutstein, Z. A Fayad, and V. Fuster Predicting plaque rupture: enhancing diagnosis and clinical decision-making in coronary artery disease Vascular Medicine, August 1, 2000; 5(3): 163 - 172. [Abstract] [PDF]

				T. Niinobu, K. Fukuo, O. Yasuda, M. Tsubakimoto, M. Mogi, H. Nishimaki, S. Morimoto, and T. Ogihara Negative feedback regulation of activated macrophages via Fas-mediated apoptosis Am J Physiol Cell Physiol, August 1, 2000; 279(2): C504 - C509. [Abstract] [Full Text] [PDF]

				B. J. Kudchodkar, J. Wilson, A. Lacko, and L. Dory Hyperbaric Oxygen Reduces the Progression and Accelerates the Regression of Atherosclerosis in Rabbits Arterioscler. Thromb. Vasc. Biol., June 1, 2000; 20(6): 1637 - 1643. [Abstract] [Full Text] [PDF]

				M. Klouche, S. Rose-John, W. Schmiedt, and S. Bhakdi Enzymatically Degraded, Nonoxidized LDL Induces Human Vascular Smooth Muscle Cell Activation, Foam Cell Transformation, and Proliferation Circulation, April 18, 2000; 101(15): 1799 - 1805. [Abstract] [Full Text] [PDF]

				A. E. Rusinol, L. Yang, D. Thewke, S. R. Panini, M. F. Kramer, and M. S. Sinensky Isolation of a Somatic Cell Mutant Resistant to the Induction of Apoptosis by Oxidized Low Density Lipoprotein J. Biol. Chem., March 15, 2000; 275(10): 7296 - 7303. [Abstract] [Full Text] [PDF]

				J. Lemay, P. Hamet, and D. deBlois Losartan-induced apoptosis as a novel mechanism for the prevention of vascular lesion formation after injury Journal of Renin-Angiotensin-Aldosterone System, March 1, 2000; 1(1): 46 - 50. [Abstract] [PDF]

				M. MAYR, C. LI, Y. ZOU, U. HUEMER, Y. HU, and Q. XU Biomechanical stress-induced apoptosis in vein grafts involves p38 mitogen-activated protein kinases FASEB J, February 1, 2000; 14(2): 261 - 270. [Abstract] [Full Text]

				D. S. O’Connor, J. S. Schechner, C. Adida, M. Mesri, A. L. Rothermel, F. Li, A. K. Nath, J. S. Pober, and D. C. Altieri Control of Apoptosis during Angiogenesis by Survivin Expression in Endothelial Cells Am. J. Pathol., February 1, 2000; 156(2): 393 - 398. [Abstract] [Full Text] [PDF]