© 1998 American Heart Association, Inc.
Brief Reviews |
Apoptosis in the Atherosclerotic Plaque
Quantitative and Qualitative Aspects
From the Department of Pathology AZ-Middelheim and Division of Pharmacology, University of Antwerp, Antwerp, Belgium.
Correspondence to Dr M. Kockx, Department of Pathology, AZ Middelheim, Lindendreef, 1, B-2020 Antwerp, Belgium. E-mail mark.kockx{at}uia.ua.ac.be
Abstract
Abstract—Several laboratories
have demonstrated the presence of apoptotic cell death in
atherosclerotic plaques. Apoptosis occurs in at least 2 stages.
The final "execution" phase, which includes DNA fragmentation, is
brief (
6 hours) and irreversible and can be detected by the terminal
deoxynucleotidyl transferase–mediated dUTP nick
end labeling (TUNEL) technique. The TUNEL technique is only selective
(rather than specific) for apoptotic nuclei, because these
contain a far greater degree of DNA fragmentation than do
nonapoptotic nuclei. Nonapoptotic cell nuclei that show
high levels of RNA synthesis and splicing can also be labeled. This
could explain the large variation in the reported percentages of
TUNEL-positive nuclei in the plaques. Therefore, the TUNEL technique
should be combined with additional techniques, such as markers of
transcription and morphological criteria. Recent studies
indicate that human fatty streaks differ from adaptive intimal
thickenings by the presence of cells containing pro-apoptotic
proteins. However, apoptotic cell death is present only in
advanced atherosclerotic plaques that show a dense macrophage
infiltration. This indicates that although both smooth muscle cells and
macrophages within the human fatty streaks become susceptible
to apoptosis, additional factors (mainly macrophage-
and lipid-derived factors) are necessary to terminate the cell
death pathway.
Key Words: atherosclerosis • apoptosis • BAX • TUNEL • lipids
Apoptosis: Definition, Detection Methods, and Their Possible Pitfalls
Kerr et al1 have introduced the term "apoptosis" to distinguish a special form of cell death different from necrosis. Apoptotic cell death is characterized by a series of morphological changes detectable by light and electron microscopy, starting from the shrinkage of the cell membrane, to condensation of nuclear chromatin, cellular fragmentation, and finally the engulfment of the apoptotic bodies by neighboring cells.
Although the term apoptosis was introduced only 25 years ago, typically apoptotic morphology was described by embryologists at the beginning of this century. Embryologists recognized apoptosis as a mechanism to counterbalance the excess cellular proliferation during the development of organs and limbs.2 More recently, apoptosis has also been implicated in the development of arteries. Cho et al3 have studied apoptosis during lamb vessel development, and Slomp et al4 focused on apoptosis during the remodeling of human ductus arteriosus. Apoptosis, however, is not limited to cell elimination during embryonic development. In recent years, apoptosis has been implicated in cardiovascular disease. We want to focus on the detection of apoptosis in the atherosclerotic plaque.
The initial description of apoptosis was based on morphological features. Several useful biochemical and immunohistochemical detection methods were subsequently introduced. Wyllie5 in 1980 described fragmentation of nuclear DNA into multiples of 180 bp as the result of endonuclease activation. When fragmented DNAs were electrophoresed in an agarose gel, they separated into a characteristic DNA "ladder" pattern.5 6 7 Gavrieli et al8 described another widely used method, in which DNA breaks in apoptotic nuclei were marked by dUTP-biotin transferred to the free 3'-end of the cleaved DNA. Because terminal deoxynucleotidyl transferase (Tdt) was used to transfer dUTP-biotin by nick end labeling, a more convenient acronym, TUNEL, was coined to describe this procedure.
Recently, the detection of DNA fragmentation by the use of the TUNEL technique or in situ nick translation has become a standard technique for the detection of apoptosis in tissue sections. This technique is particularly interesting in those diseases that are characterized by low values of cell replication and cell death (eg, the formation of atherosclerotic plaques, which are characterized by slow progression).
Although the TUNEL technique is a widespread procedure to detect apoptosis, it is prone to some pitfalls. It was demonstrated that the TUNEL technique could label nonnuclear structures in atherosclerotic plaques.9 This problem can be avoided by pretreatment of the histological sections with either EDTA or citric acid. The ultrastructural equivalents of these nonnuclear structures are cytoplasmic remnants that can calcify. The vesicles are similar to matrix vesicles that are present in the cartilage epiphysis of long bones.
Another drawback of the TUNEL technique is that nuclei can be labeled nonspecifically due to the proteinase K pretreatment or differences in fixation and prefixation times. In accordance with Hegyi et al,10 we also found that the technique is very sensitive and therefore needs careful titration of proteolytic pretreatment and Tdt concentration, otherwise a high fraction of nonapoptotic nuclei will be labeled. In a recent study, a molecular explanation for this phenomenon was found.11 It was demonstrated in this study that besides apoptotic nuclei, nonapoptotic nuclei that show signs of active gene transcription are labeled by the TUNEL technique. These cells are still active and are transcribing genes that might be related or completely unrelated to the apoptotic cell death pathway. In a true apoptotic cell, the nuclear DNA is cleaved in oligonucleosome-sized fragments, and processes like RNA transcription and splicing are abolished. Moreover, even in the early "execution" phase of apoptosis, caspases (CPP-32 and ICH-1L) cleave the 70-kDa protein component of splicing factor U1 small nuclear ribonucleoprotein.12 The loss of RNA splicing can be considered as an early step in the execution phase of apoptosis. Therefore, it is evident that nuclei that are TUNEL-positive and show signs of high RNA synthesis and splicing activity are clearly not in the execution phase of apoptosis. In general, these nuclei also do not show the classic criteria of apoptosis. The fact that the TUNEL technique labels nuclei with high RNA synthetic activity is not surprising, since in the past, several groups have employed a modification of the DNA in situ nick translation method to allow the in situ detection of sites of active gene transcription.13 14
Therefore, the TUNEL technique, though useful for detecting the execution phase of apoptosis, should always be combined with additional techniques such as markers of transcription and morphological criteria.
Apoptosis in Atherosclerotic Plaques: Which Values Can We Trust?
Different studies have demonstrated that cells can die in atherosclerotic plaques through apoptosis. However, a large variation in the percentage of TUNEL-positive nuclei has been found, ranging from <2%15 16 17 up to 30%.18 19 20 In a recent article, values up to even 60% have been reported.21 The TUNEL technique labels the execution phase of apoptosis, which in cell culture takes <6 hours. Some of the reported values would indicate that plaques are in an imminent state of collapse, which is certainly not the case, as remarked by Newby and George.22 This suggests that the TUNEL technique is not without pitfalls as already discussed in the previous paragraph. However, it is now without doubt that cells can die within atherosclerotic plaques through apoptosis.
Another important item is that the level of apoptotic cell
death is strongly related to the stage of development of the
atherosclerotic plaque. Therefore, large variability can be expected
when atherosclerotic plaques of different stages are compared. In
general, adaptive intimal thickening and fatty streaks show very little
apoptosis, whereas advanced atherosclerotic plaques show foci
of apoptosis (the Figure
). Most
of these foci are associated with regions of macrophage
infiltration.
|
Isner et al15 and Han et al19 found evidence for apoptotic cell death in primary atherosclerotic lesions and restenotic lesions. Apoptotic cell death was positively linked to cell replication. Restenotic lesions, showing high replication rates, also demonstrated more apoptotic nuclei. Bennett et al23 showed in an in vitro study that proliferating smooth muscle cells (SMCs) show more apoptotic cell death than do nonproliferating SMCs. A similar result was found by Bochaton-Piallat et al24 in the intimal thickening induced after endothelial denudation of the rat aorta. Bauriedel et al,25 however, found that human restenotic intimal thickenings showed less apoptotic cell death than did primary advanced human atherosclerotic plaques. A major difference could be the presence of replicating foam cells of macrophage origin in advanced human atherosclerotic plaques.26 In a study of vein graft atherosclerosis, which is considered a form of accelerated human atherosclerosis, a consistent association was found between foam cell accumulation and SMC death in the fibrous cap.27 These findings confirm the studies of Imai and Thomas28 of diet-induced lesions in cerebral atherosclerosis in swine that were published some 25 years ago. These authors studied the induced atherosclerotic lesions extensively by transmission electron microscopy and found SMC death in the plaques. These authors described these changes as necrosis of the cells, although their description of the nuclear and cytoplasmic changes fulfilled the criteria of apoptotic cell death.
Apoptosis in Atherosclerotic Plaques: Which Cell Type?
The significance of apoptotic cell death of
macrophages and SMCs could be very different. The disappearance
of macrophages by apoptosis could have a positive
effect on plaque stabilization. Indeed, the death of
macrophages would lead to decreased breakdown of the collagen
fibers. On the contrary, the disappearance of SMCs from the fibrous cap
or other vulnerable regions of the plaque could lead to destabilization
of the plaque.29 30 Therefore, it is essential in
studies on apoptosis in atherosclerosis to
clearly define which cell type is involved. This discernment, however,
is not always possible, since most of the apoptotic cells lose
their differentiation markers during the process of apoptosis.
Björkerud and Björkerud20 have found
that macrophages, as well as lymphocytes and SMCs, can be
labeled by the TUNEL technique in atherosclerotic plaques. Geng and
Libby18 and Han et al19
have found similar results, which indicate that both
macrophages and SMCs can die in atherosclerotic plaques through
apoptosis. We have recently confirmed that the TUNEL-positive
nuclei and nuclear fragments belong to macrophages and
SMCs.31 However, a significant fraction of the
labeled nuclei and nuclear fragments could not be stained by CD68 or
-SMC actin, which could reflect a loss of specific markers during
apoptosis. A feature of SMCs in atherosclerotic plaques is that
they are surrounded by "cages" of thickened basal lamina
(pancakelike SMCs).32 Basal lamina and basement
membranes can be stained with a periodic acid–Schiff (PAS) stain. By
combining the TUNEL technique with a PAS stain, we could detect
TUNEL-labeled nuclei and nuclear fragments that were enclosed by a cage
of PAS-positive material, indicating smooth muscle apoptosis.
Moreover, clusters of TUNEL-negative cytoplasmic remnants, which were
enclosed by thickened basal laminas, were present. Transmission
electron microscopy confirmed the presence of small, membrane-bound
vesicles of varying size that were shed from SMCs and the SMCs that had
died by disintegration into a myriad of vesicles. These vesicles were
enclosed by prominent cages of basal lamina. These vesicles are similar
to the granulovesicular degeneration of SMCs present in cerebral
atherosclerosis, as described by Stehbens >20 years
ago.33
Are SMCs "Programmed" to Die Within the Atherosclerotic Plaque?
Another important consideration is that although the SMCs in the atherosclerotic plaques are programmed to die, additional factors are necessary for completing the cell death pathway. This concept is suggested by the interesting finding that SMCs derived from the atherosclerotic plaque but not from the media die when brought into culture.34 In a recent study by our group, it was demonstrated that SMCs of human fatty streaks differed from the media and adaptive intimal thickenings by the presence of BAX, a pro-apoptotic protein of the BCL-2 family.31 It was not evident which factor heterodimerized with BAX, since BCL-2 could not be detected. Recent data demonstrate that BCL-Xl could be involved. BCL-X is present in the media of normal rat arteries.35 Interestingly, Pollman et al36 induced apoptosis in the plaques by the use of an antisense probe against the mRNA of BCL-Xl.
The presence of BAX in human fatty streaks31
indicates that both SMCs and macrophages are programmed to die
but that an additional factor is necessary to start the execution phase
of apoptosis (the Figure
). This execution phase, which is
detected by the TUNEL technique, was not detectable in the fatty
streaks but was frequent (up to 2%) in the advanced atherosclerotic
plaques.31 Interestingly, Mallat et
al21 found a colocalization of caspase 3 (CPP-32)
and apoptotic cells in advanced human atherosclerotic plaques.
This fits well with the concept that the caspases (especially caspases
2 and 3) are the "executioners" of the apoptotic cell death
pathway.37 The Fas system has also been studied
in atherosclerotic plaques.38 39 40 Vascular SMCs
express Fas constitutively, but the presence of the Fas ligand in
certain regions could lead to apoptotic cell death in
vulnerable regions of the plaque. Interestingly, Han et
al39 have found that some SMCs decrease their Fas
expression in atherosclerotic plaques, which could lead to a resistance
to cell death via the Fas system.
This latter scenario is a good example to illustrate that apoptosis is regulated in mammalian cells by multiple factors, either pro-life or pro-death.41 We suspect that SMCs within the atherosclerotic plaque become programmed to die (commitment phase) and that additional factors (mainly macrophage- and lipid-derived products)42 43 44 45 46 47 are focally present in the plaque that terminate the cell death program (execution phase).
Acknowledgments
This work was supported by a grant from the Flemish Fund for Scientific Research (FWO). M. Kockx is a holder of a fund for fundamental clinical research of the FWO.
Received February 26, 1998; accepted April 16, 1998.
References
1. Kerr JFR, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide ranging implications in tissue kinetics. Br J Cancer. 1972;26:239–257.[Medline] [Order article via Infotrieve]
2.
Saunders JW. Death in embryonic systems.
Science. 1966;154:604–612.
3.
Cho A, Cantman DW, Langille BL. Apoptosis
(programmed cell death) in arteries of the neonatal lamb. Circ
Res. 1995;76:168–175.
4.
Slomp J, Gittenberger-de Groot AC, Glukhova MA, van
Munsteren JC, Kockx MM, Schwartz SM, Koteliansky VE. Differentiation,
dedifferentiation, and apoptosis of smooth muscle cells during
the development of the human ductus arteriosus. Arterioscler
Thromb Vasc Biol.. 1997;17:1003–1009.
5. Wyllie AH. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature. 1980;284:555–556.[Medline] [Order article via Infotrieve]
6. Arends MJ, Morris RG, Wyllie AH. Apoptosis: the role of the endonuclease. Am J Pathol. 1990;136:593–608.[Abstract]
7. Wyllie AH, Morris RG, Smith A, Dunlop D. Chromatin cleavage in apoptosis: association with condensed chromatin morphology and dependence on macromolecular synthesis. J Pathol. 1984;142:67–77.[Medline] [Order article via Infotrieve]
8.
Gavrieli Y, Sherman Y, Ben-Sasson SA. Identification
of programmed cell death in situ via specific labeling of nuclear DNA
fragmentation. J Cell Biol. 1992;119:493–501.
9. Kockx MM, Muhring J, Bortier H, De Meyer GRY, Jacob W. Biotin or digoxigenin conjugated nucleotides bind to matrix vesicles in atherosclerotic plaques. Am J Pathol. 1996;148:1771–1777.[Abstract]
10. Hegyi L, Hardwick SJ, Mitchinson MJ. The presence of apoptotic cells in human atherosclerotic lesions. Am J Pathol. 1997;150:371–373.[Medline] [Order article via Infotrieve]
11. Kockx MM, Muhring J, Knaapen MWM, De Meyer GRY. RNA synthesis and splicing interfere with DNA in situ end labeling techniques used to detect apoptosis. Am J Pathol. 1998;152:885–888.[Abstract]
12.
Casciola-Rosen LA, Miller DK, Anhalt GJ, Rosen A.
Specific cleavage of the 70-kDa protein component of the U1 small
nuclear ribonucleoprotein is a characteristic biochemical feature of
apoptotic cell death. J Biol Chem. 1994;269:30757–30760.
13. Murer-Orlando ML, Peterson AC. In situ nick translation of human and mouse chromosomes detected with biotinylated nucleotide. Exp Cell Res. 1985;157:322–334.[Medline] [Order article via Infotrieve]
14. Adolph S, Hamaster H. In situ nick translation of metaphase chromosomes with biotin-labelled d-UTP. Hum Genet.. 1985;69:117–121.[Medline] [Order article via Infotrieve]
15.
Isner JM, Kearney M, Bortman S, Passeri J.
Apoptosis in human atherosclerosis and
restenosis. Circulation. 1995;91:2703–2711.
16. Hegyi L, Skepper JN, Cary NR, Mitchinson MJ. Foam cell apoptosis and the development of the lipid core of human atherosclerosis. J Pathol. 1996;180:423–429.[Medline] [Order article via Infotrieve]
17. Kockx MM, De Meyer GRY, Muhring J, Bult H, Bultinck J, Herman A. Distribution of cell replication and apoptosis in atherosclerotic plaques of cholesterol-fed rabbits. Atherosclerosis. 1996;120:115–124.[Medline] [Order article via Infotrieve]
18. Geng Y-J, Libby P. Evidence for apoptosis in advanced human atheroma: colocalization with interleukin 1ß converting enzyme. Am J Pathol. 1995;147:251–266.[Abstract]
19. Han DKM, 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.[Abstract]
20. Björkerud S, Björkerud 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.[Abstract]
21.
Mallat Z, Ohan J, Lesèche G, Tedgui A.
Colocalization of CPP-32 with apoptotic cells in human
atherosclerotic plaques. Circulation. 1997;96:424–428.
22. Newby AC, George SJ. Proliferation, migration, matrix turnover and death of smooth muscle cells in native coronary and vein graft atherosclerosis. Curr Opin Cardiol. 1996;11:574–582.[Medline] [Order article via Infotrieve]
23.
Bennett MR, Evan GI, Newby AC. Deregulated expression
of the c-myc oncogene abolishes inhibition of proliferation
of rat vascular smooth muscle cells by serum reduction,
interferon-gamma, heparin, and cyclic nucleotide analogues
and induces apoptosis. Circ Res. 1994;74:525–536.
24. Bochaton-Piallat ML, Gabbiani F, Redard M, Desmoulière A, Gabbiani G. Apoptosis participates in cellularity regulation during rat aortic intimal thickening. Am J Pathol. 1995;146:1059–1064.[Abstract]
25.
Bauriedel G, Schluckebier, Hutter R, Schmücking
I, Welsch U, Kandolf R, Lüderitz B, Prescott MF.
Apoptosis in restenosis versus stable angina
atherosclerosis: implications for the pathogenesis of
restenosis. Arterioscler Thromb Vasc Biol. 1998;18:1132–1139.
26.
Ihling C, Menzel G, Wellens E, Mönting JS,
Schaeffer HE, Zeiher AM. Topographical association between
cyclin-dependent kinase inhibitor p21, p53 accumulation,
and cellular proliferation in human atherosclerotic tissue.
Arterioscler Thromb Vasc Biol. 1997;17:2218–2224.
27.
Kockx MM, De Meyer GRY, Bortier H, de Meyere N, Muhring
J, Bakker A, Jacob W, Van Vaeck L, Herman A. Luminal foam cell
accumulation is associated with smooth muscle cell death in the intimal
thickening of human saphenous vein grafts. Circulation. 1996;94:1255–1262.
28. Imai H, Thomas WA. Cerebral atherosclerosis in swine: role of necrosis in progression of diet-induced lesions from proliferative to atheromatous stage. Exp Mol Pathol. 1968;8:330–357.[Medline] [Order article via Infotrieve]
29.
Davies MJ. Stability and instability: two faces of
coronary atherosclerosis.
Circulation. 1996;94:2013–2020.
30. Libby P, Geng YJ, Aikawa M, Schoenbeck U, Mach F, Clinton SK, Sukhova GK, Lee RT. Macrophages and atherosclerotic plaque stability. Curr Opin Lipidol. 1996;7:330–335.[Medline] [Order article via Infotrieve]
31.
Kockx MM, De Meyer GRY, Muhring J, Jacob W, Bult H,
Herman AG. Apoptosis and related proteins in different stages
of human atherosclerotic plaques. Circulation.. 1998;97:2307–2315.
32. Ross R, Wight TN, Strandness E, Thiele B. Human atherosclerosis, I: cell constitution and characteristics of advanced lesions of the superficial femoral artery. Am J Pathol. 1984;114:79–93.[Abstract]
33. Stehbens WE. Cerebral atherosclerosis: intimal proliferation and atherosclerosis in the cerebral arteries. Arch Pathol. 1975;999:582–591.
34. 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.
35.
Perlman H, Maillard L, Krasinski K, Walsh K. Evidence
for the rapid onset of apoptosis in medial smooth muscle cells
after balloon injury. Circulation. 1997;95:981–987.
36. Pollman MJ, Hall JL, Mann MJ, Zhang L, Gibbons GH. Inhibition of neointimal cell bcl-x expression induces apoptosis and regression of vascular disease. Nat Med. 1998;4:222–227.[Medline] [Order article via Infotrieve]
37. Salvesen GS, Dixit VM. Caspases: intracellular signalling by proteolysis. Cell. 1997;91:443–446.[Medline] [Order article via Infotrieve]
38.
Geng YJ, Henderson LE, Levesque EB, Muszynski M, Libby
P. Involvement of the Fas death-signalling pathway in
cytokine-induced apoptosis of vascular smooth
muscle cells during atherogenesis. Arterioscler Thromb Vasc
Biol. 1997;17:2200–2208.
39. Han DKM, Wright ME, Dixit VM, Pruit R, Son Soe M, Lynch DH, Schwartz SM. Evidence for escape of apoptosis by a loss of Fas in atherosclerotic plaque smooth muscle cells. Circulation. 1996;94(suppl I):I-397.
40. 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.[Medline] [Order article via Infotrieve]
41.
Yeh ETH. Life and death in the
cardiovascular system. Circulation. 1997;95:782–786.
42. Reid VC, Hardwick SJ, Mitchinson MJ. Fragmentation of DNA in P388 D1 macrophages exposed to oxidised low density lipoprotein. FEBS Lett.. 1993;332:218–220.
43. Matthys KE, Bult H. Nitric oxide function in atherosclerosis. Med Inflammat.. 1997;6:3–21.
44.
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.
45.
Dimmeler S, Haendeler J, Galle J, Zeiher AM. Oxidized
low density lipoprotein induces apoptosis of human
endothelial cells by activation of CPP-32 like
proteases. Circulation. 1997;95:1760–1763.
46. Lizard G, Lemaire S, Monier S, Gueldry S, Neel D, Gambert P. Induction of apoptosis and of interleukin-1ß secretion by 7ß-hydroxycholesterol and 7-ketocholesterol: partial inhibition by Bcl-2 overexpression. FEBS Lett. 1997;419:276–280.[Medline] [Order article via Infotrieve]
47. Nishio E, Watanabe Y. Oxysterols induced apoptosis in cultured smooth muscle cells through CPP32 protease activation and BCL-2 protein downregulation. Biochem Biophys Res Commun. 1996;226:928–934.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  E. Thorp and I. Tabas Mechanisms and consequences of efferocytosis in advanced atherosclerosis J. Leukoc. Biol., November 1, 2009; 86(5): 1089 - 1095. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Mayr, D. Grainger, U. Mayr, A. S. Leroyer, G. Leseche, A. Sidibe, O. Herbin, X. Yin, A. Gomes, B. Madhu, et al. Proteomics, Metabolomics, and Immunomics on Microparticles Derived From Human Atherosclerotic Plaques Circ Cardiovasc Genet, August 1, 2009; 2(4): 379 - 388. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Yang, D. Gagarin, G. St. Laurent III, N. Hammell, I. Toma, C.-a. Hu, A. Iwasa, and T. A. McCaffrey Cardiovascular Inflammation and Lesion Cell Apoptosis: A Novel Connection via the Interferon-Inducible Immunoproteasome Arterioscler Thromb Vasc Biol, August 1, 2009; 29(8): 1213 - 1219. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Wang, W. Zhang, C. Zhu, C. Bucher, B. R. Blazar, C. Zhang, J.-F. Chen, J. Linden, C. Wu, and Y. Huo Inactivation of the Adenosine A2A Receptor Protects Apolipoprotein E-Deficient Mice From Atherosclerosis Arterioscler Thromb Vasc Biol, July 1, 2009; 29(7): 1046 - 1052. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Thorp, Y. Li, L. Bao, P. M. Yao, G. Kuriakose, J. Rong, E. A. Fisher, and I. Tabas Brief Report: Increased Apoptosis in Advanced Atherosclerotic Lesions of Apoe-/- Mice Lacking Macrophage Bcl-2 Arterioscler Thromb Vasc Biol, February 1, 2009; 29(2): 169 - 172. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. S. Leroyer, P.-E. Rautou, J.-S. Silvestre, Y. Castier, G. Leseche, C. Devue, M. Duriez, R. P. Brandes, E. Lutgens, A. Tedgui, et al. CD40 Ligand+ Microparticles From Human Atherosclerotic Plaques Stimulate Endothelial Proliferation and Angiogenesis: A Potential Mechanism for Intraplaque Neovascularization J. Am. Coll. Cardiol., October 14, 2008; 52(16): 1302 - 1311. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W.-S. Lim, J. M. Timmins, T. A. Seimon, A. Sadler, F. D. Kolodgie, R. Virmani, and I. Tabas Signal Transducer and Activator of Transcription-1 Is Critical for Apoptosis in Macrophages Subjected to Endoplasmic Reticulum Stress In Vitro and in Advanced Atherosclerotic Lesions In Vivo Circulation, February 19, 2008; 117(7): 940 - 951. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Thorp, G. Kuriakose, Y. M. Shah, F. J. Gonzalez, and I. Tabas Pioglitazone Increases Macrophage Apoptosis and Plaque Necrosis in Advanced Atherosclerotic Lesions of Nondiabetic Low-Density Lipoprotein Receptor Null Mice Circulation, November 6, 2007; 116(19): 2182 - 2190. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Puato, C. Piergentili, M. Zanardo, R. Rocchi, M. Giordan, P. Cardaioli, and P. Pauletto Vascular Remodeling After Carotid Artery Stenting Angiology, November 1, 2007; 58(5): 565 - 571. [Abstract] [PDF]
|
|
|
|
|
|
D. Cui, E. Thorp, Y. Li, N. Wang, L. Yvan-Charvet, A. R. Tall, and I. Tabas Pivotal Advance: Macrophages become resistant to cholesterol-induced death after phagocytosis of apoptotic cells J. Leukoc. Biol., November 1, 2007; 82(5): 1040 - 1050. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Qiao, M. Kisgati, J. M. Cholewa, W. Zhu, E. J. Smart, M. S. Sulistio, and R. Asmis Increased Expression of Glutathione Reductase in Macrophages Decreases Atherosclerotic Lesion Formation in Low-Density Lipoprotein Receptor-Deficient Mice Arterioscler Thromb Vasc Biol, June 1, 2007; 27(6): 1375 - 1382. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Stoneman, D. Braganza, N. Figg, J. Mercer, R. Lang, M. Goddard, and M. Bennett Monocyte/Macrophage Suppression in CD11b Diphtheria Toxin Receptor Transgenic Mice Differentially Affects Atherogenesis and Established Plaques Circ. Res., March 30, 2007; 100(6): 884 - 893. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. Leroyer, H. Isobe, G. Leseche, Y. Castier, M. Wassef, Z. Mallat, B. R. Binder, A. Tedgui, and C. M. Boulanger Cellular Origins and Thrombogenic Activity of Microparticles Isolated From Human Atherosclerotic Plaques J. Am. Coll. Cardiol., February 20, 2007; 49(7): 772 - 777. [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]
|
|
|
|
|
|
P. Secchiero, R. Candido, F. Corallini, S. Zacchigna, B. Toffoli, E. Rimondi, B. Fabris, M. Giacca, and G. Zauli Systemic Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Delivery Shows Antiatherosclerotic Activity in Apolipoprotein E-Null Diabetic Mice Circulation, October 3, 2006; 114(14): 1522 - 1530. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. R. Brunt, K. K. Fenrich, G. Kiani, M. Yat Tse, S. C. Pang, C. A. Ward, and L. G. Melo Protection of Human Vascular Smooth Muscle Cells From H2O2-Induced Apoptosis Through Functional Codependence Between HO-1 and AKT Arterioscler Thromb Vasc Biol, September 1, 2006; 26(9): 2027 - 2034. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Rosner, V. Stoneman, T. Littlewood, N. McCarthy, N. Figg, Y. Wang, G. Tellides, and M. Bennett Interferon-{gamma} Induces Fas Trafficking and Sensitization to Apoptosis in Vascular Smooth Muscle Cells via a PI3K- and Akt-Dependent Mechanism Am. J. Pathol., June 1, 2006; 168(6): 2054 - 2063. [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]
|
|
|
|
 |
|
 E. J. Ryer, K. Sakakibara, C. Wang, D. Sarkar, P. B. Fisher, P. L. Faries, K. C. Kent, and B. Liu Protein Kinase C Delta Induces Apoptosis of Vascular Smooth Muscle Cells through Induction of the Tumor Suppressor p53 by Both p38-dependent and p38-independent Mechanisms J. Biol. Chem., October 21, 2005; 280(42): 35310 - 35317. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. DeVries-Seimon, Y. Li, P. M. Yao, E. Stone, Y. Wang, R. J. Davis, R. Flavell, and I. Tabas Cholesterol-induced macrophage apoptosis requires ER stress pathways and engagement of the type A scavenger receptor J. Cell Biol., October 10, 2005; 171(1): 61 - 73. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. G. Herman and S. Moncada Therapeutic potential of nitric oxide donors in the prevention and treatment of atherosclerosis Eur. Heart J., October 1, 2005; 26(19): 1945 - 1955. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Binder, P. X. Shaw, M.-K. Chang, A. Boullier, K. Hartvigsen, S. Horkko, Y. I. Miller, D. A. Woelkers, M. Corr, and J. L. Witztum Thematic review series: The Immune System and Atherogenesis. The role of natural antibodies in atherogenesis J. Lipid Res., July 1, 2005; 46(7): 1353 - 1363. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Koutsouki, C. A. Beeching, S. C. Slater, O. W. Blaschuk, G. B. Sala-Newby, and S. J. George N-Cadherin-Dependent Cell-Cell Contacts Promote Human Saphenous Vein Smooth Muscle Cell Survival Arterioscler Thromb Vasc Biol, May 1, 2005; 25(5): 982 - 988. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Halvorsen, T. Waehre, H. Scholz, O. P. Clausen, J. H. von der Thusen, F. Muller, H. Heimli, S. Tonstad, C. Hall, S. S. Froland, et al. Interleukin-10 enhances the oxidized LDL-induced foam cell formation of macrophages by antiapoptotic mechanisms J. Lipid Res., February 1, 2005; 46(2): 211 - 219. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. L. Raffai, S. M. Loeb, and K. H. Weisgraber Apolipoprotein E Promotes the Regression of Atherosclerosis Independently of Lowering Plasma Cholesterol Levels Arterioscler Thromb Vasc Biol, February 1, 2005; 25(2): 436 - 441. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. C. Tung, G. Cui, K. Oshima, H. Laks, and L. Sen Balanced expression of mitochondrial apoptosis regulatory proteins correlates with long-term survival of cardiac allografts Am J Physiol Heart Circ Physiol, December 1, 2003; 285(6): H2832 - H2841. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Feng, D. Zhang, G. Kuriakose, C. M. Devlin, M. Kockx, and I. Tabas Niemann-Pick C heterozygosity confers resistance to lesional necrosis and macrophage apoptosis in murine atherosclerosis PNAS, September 2, 2003; 100(18): 10423 - 10428. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-W. Chien, C.-S. Chien, L.-D. Hsiao, C.-H. Lin, and C.-M. Yang OxLDL induces mitogen-activated protein kinase activation mediated via PI3-kinase/Akt in vascular smooth muscle cells J. Lipid Res., September 1, 2003; 44(9): 1667 - 1675. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Hundal, A. Gomez-Munoz, J. Y. Kong, B. S. Salh, A. Marotta, V. Duronio, and U. P. Steinbrecher Oxidized Low Density Lipoprotein Inhibits Macrophage Apoptosis by Blocking Ceramide Generation, Thereby Maintaining Protein Kinase B Activation and Bcl-XL Levels J. Biol. Chem., June 27, 2003; 278(27): 24399 - 24408. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. D. Johnson, Y. Balagurunathan, K. P. Lu, M. Tadesse, M. H. Falahatpisheh, R. J. Carroll, E. R. Dougherty, C. A. Afshari, and K. S. Ramos Genomic profiles and predictive biological networks in oxidant-induced atherogenesis Physiol Genomics, May 13, 2003; 13(3): 263 - 275. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Wernig, M. Mayr, and Q. Xu Mechanical Stretch-Induced Apoptosis in Smooth Muscle Cells Is Mediated by {beta}1-Integrin Signaling Pathways Hypertension, April 1, 2003; 41(4): 903 - 911. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Martinet, M. W.M. Knaapen, G. R.Y. De Meyer, A. G. Herman, and M. M. Kockx Overexpression of the Anti-Apoptotic Caspase-2 Short Isoform in Macrophage-Derived Foam Cells of Human Atherosclerotic Plaques Am. J. Pathol., March 1, 2003; 162(3): 731 - 736. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Valgimigli, L. Agnoletti, S. Curello, L. Comini, G. Francolini, F. Mastrorilli, E. Merli, R. Pirani, G. Guardigli, P. G. Grigolato, et al. Serum From Patients With Acute Coronary Syndromes Displays a Proapoptotic Effect on Human Endothelial Cells: A Possible Link to Pan-Coronary Syndromes Circulation, January 21, 2003; 107(2): 264 - 270. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Werner and G. Nickenig AT1 receptors in atherosclerosis: biological effects including growth, angiogenesis, and apoptosis Eur. Heart J. Suppl., January 1, 2003; 5(suppl_A): A9 - A13. [Abstract] [PDF]
|
|
|
|
 |
|
 D. G.M Molin, M. C DeRuiter, L. J Wisse, M. Azhar, T. Doetschman, R. E Poelmann, and A. C Gittenberger-de Groot Altered apoptosis pattern during pharyngeal arch artery remodelling is associated with aortic arch malformations in Tgf{beta}2 knock-out mice Cardiovasc Res, November 1, 2002; 56(2): 312 - 322. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. R Bennett APOPTOSIS IN THE CARDIOVASCULAR SYSTEM Heart, May 1, 2002; 87(5): 480 - 487. [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Hunt, R. Fairman, M. E. Mitchell, J. P. Carpenter, M. Golden, T. Khalapyan, M. Wolfe, D. Neschis, R. Milner, B. Scoll, et al. Bone Formation in Carotid Plaques: A Clinicopathological Study Stroke, May 1, 2002; 33(5): 1214 - 1219. [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. Y. Kim, H. K. Shin, J. M. Choi, and K. W. Hong Inhibition of Lipopolysaccharide-Induced Apoptosis by Cilostazol in Human Umbilical Vein Endothelial Cells J. Pharmacol. Exp. Ther., February 1, 2002; 300(2): 709 - 715. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Niemann-Jonsson, M. P.S. Ares, Z.-Q. Yan, D.-X. Bu, G. N. Fredrikson, L. Branen, I. Porn-Ares, A. H. Nilsson, and J. Nilsson Increased Rate of Apoptosis in Intimal Arterial Smooth Muscle Cells Through Endogenous Activation of TNF Receptors Arterioscler Thromb Vasc Biol, December 1, 2001; 21(12): 1909 - 1914. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. X. Rong, J. Li, E. D. Reis, R. P. Choudhury, H. M. Dansky, V. I. Elmalem, J. T. Fallon, J. L. Breslow, and E. A. Fisher Elevating High-Density Lipoprotein Cholesterol in Apolipoprotein E-Deficient Mice Remodels Advanced Atherosclerotic Lesions by Decreasing Macrophage and Increasing Smooth Muscle Cell Content Circulation, November 13, 2001; 104(20): 2447 - 2452. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Khurana, J. F. Martin, and I. Zachary Gene Therapy for Cardiovascular Disease: A Case for Cautious Optimism Hypertension, November 1, 2001; 38(5): 1210 - 1216. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. MERTENS and P. HOLVOET Oxidized LDL and HDL: antagonists in atherothrombosis FASEB J, October 1, 2001; 15(12): 2073 - 2084. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Mallat and A. Tedgui Current Perspective on the Role of Apoptosis in Atherothrombotic Disease Circ. Res., May 25, 2001; 88(10): 998 - 1003. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Tabas p53 and Atherosclerosis Circ. Res., April 27, 2001; 88(8): 747 - 749. [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]
|
|
|
|
|
|
D. Proudfoot, J. N. Skepper, L. Hegyi, M. R. Bennett, C. M. Shanahan, and P. L. Weissberg Apoptosis Regulates Human Vascular Calcification In Vitro : Evidence for Initiation of Vascular Calcification by Apoptotic Bodies Circ. Res., November 24, 2000; 87(11): 1055 - 1062. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Sato, K. Nair, J. Hiddinga, N. L. Eberhardt, L. A. Fitzpatrick, Z. S. Katusic, and T. O'Brien eNOS gene transfer to vascular smooth muscle cells inhibits cell proliferation via upregulation of p27 and p21 and not apoptosis Cardiovasc Res, September 1, 2000; 47(4): 697 - 706. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Neuville, M.-L. Bochaton-Piallat, and G. Gabbiani Retinoids and Arterial Smooth Muscle Cells Arterioscler Thromb Vasc Biol, August 1, 2000; 20(8): 1882 - 1888. [Full Text] [PDF]
|
|
|
|
|
|
H.-S. Liao, T. Kodama, and Y.-J. Geng Expression of Class A Scavenger Receptor Inhibits Apoptosis of Macrophages Triggered by Oxidized Low Density Lipoprotein and Oxysterol Arterioscler Thromb Vasc Biol, August 1, 2000; 20(8): 1968 - 1975. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Xu, G. Schett, H. Perschinka, M. Mayr, G. Egger, F. Oberhollenzer, J. Willeit, S. Kiechl, and G. Wick Serum Soluble Heat Shock Protein 60 Is Elevated in Subjects With Atherosclerosis in a General Population Circulation, July 4, 2000; 102(1): 14 - 20. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Xu, G. Schett, C. Li, Y. Hu, and G. Wick Mechanical Stress-Induced Heat Shock Protein 70 Expression in Vascular Smooth Muscle Cells Is Regulated by Rac and Ras Small G Proteins but Not Mitogen-Activated Protein Kinases Circ. Res., June 9, 2000; 86(11): 1122 - 1128. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Tricot, Z. Mallat, C. Heymes, J. Belmin, G. Leseche, and A. Tedgui Relation Between Endothelial Cell Apoptosis and Blood Flow Direction in Human Atherosclerotic Plaques Circulation, May 30, 2000; 101(21): 2450 - 2453. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Orlandi, M. Marcellini, and L. G. Spagnoli Aging Influences Development and Progression of Early Aortic Atherosclerotic Lesions in Cholesterol-Fed Rabbits Arterioscler Thromb Vasc Biol, April 1, 2000; 20(4): 1123 - 1136. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Tsimikas, B. P. Shortal, J. L. Witztum, and W. Palinski In Vivo Uptake of Radiolabeled MDA2, an Oxidation-Specific Monoclonal Antibody, Provides an Accurate Measure of Atherosclerotic Lesions Rich in Oxidized LDL and Is Highly Sensitive to Their Regression Arterioscler Thromb Vasc Biol, March 1, 2000; 20(3): 689 - 697. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. B. Schneider, G. Vassalli, S. Wen, R. M. Driscoll, A. B. Sassani, M. B. DeYoung, R. Linnemann, R. Virmani, and D. A. Dichek Expression of Fas Ligand in Arteries of Hypercholesterolemic Rabbits Accelerates Atherosclerotic Lesion Formation Arterioscler Thromb Vasc Biol, February 1, 2000; 20(2): 298 - 308. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M Kockx and A. G Herman Apoptosis in atherosclerosis: beneficial or detrimental? Cardiovasc Res, February 1, 2000; 45(3): 736 - 746. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P Meerarani, P Ramadass, M. Toborek, H.-C. Bauer, H. Bauer, and B. Hennig Zinc protects against apoptosis of endothelial cells induced by linoleic acid and tumor necrosis factor {alpha}1 Am. J. Clinical Nutrition, January 1, 2000; 71(1): 81 - 87. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Faggin, M. Puato, A. Chiavegato, R. Franch, P. Pauletto, and S. Sartore Fish Oil Supplementation Prevents Neointima Formation in Nonhypercholesterolemic Balloon-Injured Rabbit Carotid Artery by Reducing Medial and Adventitial Cell Activation Arterioscler Thromb Vasc Biol, January 1, 2000; 20(1): 152 - 163. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. Yao and I. Tabas Free Cholesterol Loading of Macrophages Induces Apoptosis Involving the Fas Pathway J. Biol. Chem., July 28, 2000; 275(31): 23807 - 23813. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Kavurma, F. S. Santiago, E. Bonfoco, and L. M. Khachigian Sp1 Phosphorylation Regulates Apoptosis via Extracellular FasL-Fas Engagement J. Biol. Chem., February 9, 2001; 276(7): 4964 - 4971. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-L. Wong, B. Xie, N. Beatini, P. Phu, S. Marathe, A. Johns, P. W. Gold, E. Hirsch, K. J. Williams, J. Licinio, et al. Acute systemic inflammation up-regulates secretory sphingomyelinase in vivo: A possible link between inflammatory cytokines and atherogenesis PNAS, July 18, 2000; 97(15): 8681 - 8686. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. J.M. van Vlijmen, G. Gerritsen, A. L. Franken, L. S.M. Boesten, M. M. Kockx, M. J. Gijbels, M. P. Vierboom, M. van Eck, B. van de Water, T. J.C. van Berkel, et al. Macrophage p53 Deficiency Leads to Enhanced Atherosclerosis in APOE*3-Leiden Transgenic Mice Circ. Res., April 27, 2001; 88(8): 780 - 786. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. von der Thusen, B. J.M. van Vlijmen, R. C. Hoeben, M. M. Kockx, L.M. Havekes, T. J.C. van Berkel, and E. A.L. Biessen Induction of Atherosclerotic Plaque Rupture in Apolipoprotein E-/- Mice After Adenovirus-Mediated Transfer of p53 Circulation, April 30, 2002; 105(17): 2064 - 2070. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||