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From the Department of Cardiovascular Pathology,*
Armed
Forces Institute of Pathology, Washington, DC; the Division of
Cardiovascular Diseases,
Hahnemann University
Hospital, Philadelphia, Pennsylvania; and the Department of
Pathology,
University of Maryland, Baltimore,
Maryland
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Introduction |
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Of the morphological features associated with rupture of an advanced plaque, fibrous cap thinning seems to be the most critical.7,8 The precise nature of fibrous cap destruction is unknown although recent evidence suggests that smooth muscle cell (SMC) death by apoptosis may be partly responsible.9 On the other hand, it has been proposed that ongoing apoptosis of macrophages in a stable plaque contributes to the enlargement of necrotic core (Bjorkrud) and vulnerability to rupture. The bulk of evidence of the occurrence of apoptosis in human arteries, however, is from lesions with chronic atherosclerotic disease.10-14 The information in culprit lesions associated with plaque rupture and sudden coronary death is lacking.
This study was undertaken to determine the extent of apoptosis in varying cell populations in culprit lesions with acute thrombi attributed to plaque rupture. For comparison, culprit lesions with significant stenosis without evidence of rupture and luminal thrombi (stable plaques) were examined.15 Additional studies were performed to assess the expression and activation of two mammalian death proteases, caspase-1 and -3, in association with apoptotic cells in plaque rupture.
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Materials and Methods |
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Cases of sudden coronary death were identified as part of a consultative service provided to the Office of the Chief Medical Examiner for the State of Maryland.16 Sudden coronary death was based on unexpected death, witnessed within 6 hours of the onset of symptoms, or death of a person known to be in stable condition <24-hours antemortem. A complete autopsy, including a toxicology screen, ruled out noncardiac causes of death.
Twenty-five cases of plaque rupture were collected and of these, 21 were used for DNA fragmentation staining and immunohistochemistry and four were processed for immunoblot analysis. Of the 15 stable plaques, 11 were used for DNA fragmentation staining and four were processed for immunoblot analysis; four nonatherosclerotic arteries served as controls for immunoblot studies.
Definitions
Culprit plaques were identified as those with an acute luminal
thrombus and plaque rupture or in the absence of a thrombus, the artery
with the greatest degree of luminal narrowing relative to the internal
elastic lamina.4,15
Acute plaque ruptures consisted of a
luminal platelet-fibrin thrombus continuous with an underlying
lipid-rich core. The connection between the thrombus and the lipid-rich
core was through a disrupted thin fibrous cap infiltrated by
macrophages. Stable plaque was defined as cross-sectional luminal
narrowing of 
75% with a fibrous cap >65 µm in thickness in the
absence of plaque rupture or thrombus.
Evaluation of the Hearts and Preparation of Tissue Specimens
Hearts were studied under the supervision of the medical examiner. Coronary arteries were serial sectioned at 3-mm intervals. Segments showing narrowing of >50% were submitted for histological analysis. Collected arterial specimens were immediately immersed in ice-cold medium 199. Vessels were then snap-frozen in optimal cutting temperature tissue processing medium (OCT; Miles Diagnostics, Elkhart, IN).
In Situ End-Labeling (ISEL) for DNA Fragmentation
Serial cryostat sections (6 µm) were cut and air-dried onto Superfrost microslides (Columbia Diagnostics, Inc., Springfield, VA) and stored at -70°C before use. In situ labeling of DNA fragmentation was performed using terminal deoxyribonucleotide transferase (TdT)-mediated nick end labeling based on an in situ apoptosis detection kit (TACS; Trevigen, Gaithersburg, MD). Sections were fixed for 10 minutes in neutral-buffered formalin, rinsed in phosphate-buffered saline (PBS), and incubated for 5 minutes in 0.1% Triton X-100 in 0.1% sodium citrate. Treating the slides with 0.3% hydrogen peroxide for 10 minutes inactivated endogenous peroxidase. DNA fragments were labeled with biotinylated nucleotides (dNTPs) and TdT for 1 hour at 37°C. The incorporation of biotinylated nucleotides into DNA was detected with a streptavidin-conjugated horseradish peroxidase. The chromogenic substance used to visualize the reaction was TACS Blue Label (Trevigen) which produces a blue reaction product. Sections of rat mammary glands (weaning animals) were used a positive controls for apoptosis (Oncor, Gaithersburg, MD).
Detection of Fragmented DNA by Electron Microscopy
The method of tissue processing for ultrastructural analysis and immunogold labeling was adapted from the procedure described by Berryman and Rodewald,17 and all processing steps were performed at 4°C. Semithin sections were cut, stained with toluidine blue, and examined by light microscopy for the site of rupture. Artifact-free areas showing rupture sites were selected for ultrathin section cutting.
The TdT immunogold assay was performed as above with slight modifications.18 Sections were etched for 10 minutes in absolute ethanol, rinsed in PBS, and permeabilized in CytoPore (Trevigen, Inc.). Endogenous peroxidase was quenched by immersion in 3% hydrogen peroxide in 40% methanol. Sections were then incubated in the TdT-labeling mixture in a humidified chamber at 37°C for 1 hour. The reaction was stopped and sections were then incubated overnight at 4°C with colloidal gold-streptavidin (Zymed, San Francisco, CA) for direct visualization of biotinylated dNTPs. Immunogold labeling was examined using an electron microscope (Zeiss EM 10, Germany). Omitting TdT during the procedure as the negative control checked the validity of the method.
Immunohistochemistry
Cell Populations
Frozen sections were fixed in acetone for 10 minutes at -20°C
and then air-dried. Treating the sections with 0.3% hydrogen peroxide
for 20 minutes inactivated endogenous peroxides. Sections were
incubated in protein-free block (DAKO, Carpinteria, CA) for 10 minutes
to block nonspecific binding of primary antibody. Sections were
incubated for 1 hour at room temperature with primary antibodies
against human muscle-
-actin (HHF-35, dilution 1:50; DAKO), the
macrophage marker CD68 (DAKO-CD68, KP1, dilution 1:600; DAKO) or the
T-cell marker CD3 (DAKO-UCHT1, dilution 1:150; DAKO). Primary
antibodies were labeled by a biotinylated link antibody directed
against mouse using a peroxidase-based kit (LSAB; DAKO).
Immunostains were visualized (reddish reaction product) by an
aminoethylcarbazol substrate-chromogen system (DAKO) and
counterstained with Gill’s hematoxylin.
Double-Immunohistochemistry
To identify cell types undergoing apoptosis, double-staining was performed by combining ISEL and immunohistochemistry with antibodies against actin, CD68, or CD3. Tissue sections were first stained for DNA fragmentation (as described above); however, labeling was detected using DAB as the chromogenic substrate followed by enhancement with nickel salts (brown-black reaction product). Immunostains were visualized with a red streptavidin-alkaline phosphatase substrate (Vector, Burlingame, CA); slides were then counterstained with methyl green.
Quantification of Cell Type and Apoptosis
Double-stained slides were used for quantification of cell type
and apoptosis. For each arterial section, at least 300 total cells were
counted in random high-power fields within the fibrous cap using an
eyepiece reticle with a 0.04 mm2
grid.
Quantitatively the size of the rupture site varied between cases such
that cell counts were performed in areas ranging from 0.12 to 0.20
mm2
(Figure 1)
.
Remote areas of the fibrous cap were defined as those at least 0.4 mm
away from the nearest field representing the rupture site. Care was
taken to avoid counting inflammatory cells entrapped within the
thrombus. The varying cell types are expressed as the
percentage of total cells or apoptotic nuclei. Only nuclei
with positive immunoreactivity and cell type were counted as some
failed to stain positive with macrophage, SMC, or T cell-specific
antibodies.
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Immunostaining for caspases-1 and -3 was performed as described above. To recognize caspase-1, serial cryosections were stained with a polyclonal rabbit anti-human antibody specific for the 10-kd subunit, (Clone C-20; Santa Cruz Biotechnology, Inc., Santa Cruz, CA). Caspase-3 was immunolocalized using a polyclonal rabbit anti-human antibody (DAKO) which is found to react primarily with the 32-kd proenzyme. Nonimmune rabbit serum was used as a negative control.
Electrophoresis and Immunoblot Analysis
Culprit plaques were identified by gross histological analysis using a dissection microscope and further confirmed by histological examination of adjacent sections. Atherosclerotic segments (3 to 5 mm) with and without plaque rupture and thrombi were removed and immediately placed in ice-cold M199; nonatherosclerotic vessels were collected as controls. After removal of the adventitia, samples were snap-frozen in liquid nitrogen and stored at -70°C until protein extraction.
For protein extraction, the tissue was weighed, minced with scissors, and extracted in ice-cold lysis buffer (pH 7.6) containing 50 mmol/L Tris-HCl, 15 mmol/L NaCl, 1 mmol/L phenylmethylsulfonyl fluoride, 10 µg/ml aprotonin, 10 µg/ml leupeptin, 1% Nonidet P-40, and 1 mmol/L dithiothreitol.
Proteins (50 µg per lanes) from plaque homogenates were separated on 12% sodium dodecyl sulfate-polyacrylamide gel electrophoresis mini gels and transferred to nitrocellulose membranes (Bio-Rad, Richmond, CA) using a semidry blotting system. Blocking of nonspecific binding was achieved with incubation of the membrane in 5% milk PBS, pH 7.2, containing 0.05% Tween 20. Polyclonal antibodies against caspase-1 (Upstate Biotechnology, Lake Placid, NY) or caspase-3 (Santa Cruz Biotechnology, Inc.) were used for staining. Antigen detection was performed with a chemiluminescent detection system (ECL; Amersham, Arlington Heights, IL).
Statistical Analysis
All values are expressed as the mean ± SEM. Comparisons of apoptotic index among cell types in the different regions of the plaque were performed by factorial analysis of variance (StatView 4.5; Abacus Concepts Inc., Berkeley, CA) and analyzed simultaneously with post hoc testing by the Scheffé’s procedure; statistical significance was established at P < 0.05.
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Labeling of DNA fragmentation alone was undertaken for the
detection of apoptosis by light microscopy in ruptured and stable
plaques. Overall apoptosis within the fibrous cap was more prevalent in
plaque ruptures than in stable plaques (P =
<0.001). The bulk of this difference was accounted for by the high
degree of apoptosis at plaque rupture sites (Figure 2)
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Many cells at the ruptured site demonstrated varying stages of
apoptosis with characteristic changes of nuclear chromatin condensation
and clumping, and loss of cell volume. DNA fragmentation was shown by
combined ultrastructure and ISEL using a gold conjugate. The
gold-labeled fragments were commonly found at the periphery of the
nucleus at sites of chromatin condensation in cells undergoing
apoptosis. Only occasional gold particles were noted in cells with
normal ultrastructure and were found irrespective of nuclear chromatin
material. Unlike ruptures, apoptotic cells were rarely observed in the
fibrous caps of stable plaques.
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Immunohistochemical staining of serial sections for the
identification of cell type showed that the majority of cells at the
rupture site were macrophages. Of the total number of immunoreactive
cells, 193 ± 10 per 0.1 mm2
were
macrophages; the number of smooth muscle and T cells were markedly
less, 16 ± 2 and 15 ± 5 per 0.1 mm2,
respectively. In contrast, stable plaques showed a decreased prevalence
of macrophages (30 ± 9 per 0.1 mm2,
P < 0.0001) and an increase in SMCs (80 ± 13,
P = 0.0003); T cells comprised 
3 ± 0.5 per 0.1
mm2.
Double-staining for the immunohistochemical typing of cells in
combination with in situ labeling for apoptosis showed that
apoptotic nuclei at rupture sites were essentially those of macrophages
(Figures 4 and 5)
. Apoptosis in macrophages was more
frequent at the rupture site (93 ± 8 per 0.1
mm2) as opposed to areas of intact fibrous cap
(10 ± 2 per 0.1 mm2, P =
0.03). Apoptotic smooth muscle and T lymphocytes at the rupture site
were only 5 ± 0.9 per 0.1 mm2
and 5 ±
1 per 0.1 mm2, respectively, contributing little
to the total apoptotic cell population. Conversely, stable plaques
showed a much lower frequency of apoptotic cells compared with ruptures
(Figures 2 and 4)
. The number of apoptotic nuclei expressed per 0.1
mm2
in stable plaques were 7 ± 1.2 for
macrophages, 3 ± 0.8 for SMCs, and 0.8 ± 0.4 for T
lymphocytes.
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Apoptosis at the Rupture Site Is Associated with Interleukin-1ß-Converting Enzyme Activation
Plaque rupture sites demonstrated strong immunoreactivity to
caspase-1 corresponding to regions of apoptotic macrophages (Figure 6A)
. In contrast, immunoreactivity for
caspase-3 at rupture sites was weak (not shown). In stable plaques,
areas positive for apoptotic cells, in particular regions bordering the
necrotic core showed immunoreactivity to both caspases-1 and -3 (Figure 6B)
; staining in the fibrous cap was essentially negative for either
protein.
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. In contrast,
the cleaved p20 band of caspase-1 was noted only in the
ruptured plaques. Stable plaques did not show the evidence of caspase-1
activation. Nonatherosclerotic control arterial segments failed to show
either the caspase-1 precursor or cleavage products. Unlike
interleukin-1ß-converting enzyme in plaque ruptures, caspase-3
cleavage to p17 protein was not detected in any of the cases; only the
uncleaved 32-kd band was present (data not shown). |
Discussion |
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SMC Apoptosis and the Vulnerable Plaque
There is a well-established association of rupture with thin fibrous caps19 and cap thickness constitutes a major part of the definition of the vulnerable plaque.4 Although apoptosis of SMCs, in part may lead to fibrous cap thinning, this was not appreciated in the present study perhaps because the lesions were already ruptured. The paucity of SMCs at plaque rupture sites; however, suggests that SMC death may have occurred at an earlier time point. One preliminary study suggests that human monocytes/macrophages induce vascular SMC apoptosis;20 although in fatty streaks, both appear to co-exist. The finding of decreased SMCs at plaque rupture sites agrees with earlier studies involving ulcerated lesions of the aorta.21,22 The overall loss of SMCs within the fibrous cap, most likely represents a chronic process before the actual rupture event.
Apoptosis versus Oncosis
There is at least one paper on carotid plaques suggesting that oncosis contributes to cell death.23 Recognition between apoptosis and oncosis is best appreciated at the ultrastructural level, because the terminal dUTP nick-end labeling assay by light microscopy lacks specificity. These pathways of cell death are best distinguished early because the phase of necrosis is similar for both.24 In our study, early changes of cell death showed morphological features consistent with the nuclear changes associated with apoptosis. Because of the variable uptake of lipids and differences in cell size, cell shrinkage (another feature of apoptosis), was not always apparent. There was also some degree of uncertainty of cell type, because lipid-uptake was not exclusive to macrophages. As the morphological changes of cell death advanced the distinction between apoptosis and oncosis became difficult, thus, death by oncosis could not be excluded.
Dissolution of Matrix and Cell Apoptosis Anoikis
The precise etiology of macrophage apoptosis at the plaque rupture
site is speculative. There is experimental evidence that the
dissolution of extracellular matrix may threaten cell survival. In
epithelial and vascular endothelium, inhibition of integrin function
has been shown to produce a loss of cell-cell adhesion and
apoptosis.25,26
This type of detachment-induced cell
death, a form of apoptosis, is referred to as
"anoikis."27
In another study, basement membrane
matrix was shown to suppress apoptosis of mammary
epithelial cells in tissue culture and in vivo. In
these studies, antibodies to -integrins or overexpression of
stromelysin-1 stimulated apoptosis, whereas the loss of extracellular
matrix correlated with the expression of caspase-1 such that specific
inhibitors of its activity rescued cells from apoptosis. Although data
on cell attachment and death of human macrophages is lacking, an
integrin dependence of cell survival has been shown in the murine
macrophage-like cell line RAW264.7.28
TIMP-3 and Cell Survival in the Fibrous Cap
There is emerging evidence that inhibitors of metalloproteinases, specifically TIMP-3, directly affect cell survival.29 For example, adenoviral-induced overexpression of TIMP-3 promotes apoptosis of vascular SMCs both in vivo and in vitro. Although little TIMP-3 protein is found in normal arteries, it is markedly elevated in advanced plaques and is primarily associated with intimal macrophages at rupture-prone sites.30 It remains to be demonstrated whether macrophages themselves commit cellular suicide through the expression of TIMP-3.
Apoptosis of Macrophages and Thrombogenicity
Macrophage apoptosis may also facilitate the acute thrombotic event arising from the rupture itself. In a recent study, Mallat et al31 examined the role of apoptotic cell death in relation to plaque thrombogenicity. Shed membrane microparticles, products of apoptotic cells from carotid plaques were captured by annexin V and analyzed for their procoagulant activity. These microparticles were primarily monocytic and lymphocytic in origin, and very rich in tissue factor activity. Thus, it is conceivable that microparticles from macrophage apoptosis at the rupture site may increase the procoagulant potential of the plaque.
Caspases and Cell Death in Plaques
Apoptosis in mammalian cells is essentially regulated by caspases that are homologous to the C. elegans (worm) death genes.32,33 The prototypic enzyme caspase-1 is synthesized as a 45-kd proenzyme that is autocatalytically cleaved to generate an active homodimeric enzyme of 20- and 10-kd subunits.34 Geng and Libby10 first reported on the co-localization of caspase-1 with apoptosis in advanced human atherosclerotic plaques. This data is corroborated by our study in which extensive expression of caspase-1 was detected at rupture sites rich in apoptotic macrophages. In comparison, caspase-1 immunolocalization in stable plaques was mostly confined to areas surrounding the necrotic core with minimal staining within the fibrous cap.
Although caspase-3 was also detected in ruptured plaques, its expression was not localized to plaque rupture sites and was more associated with cells surrounding the necrotic core. In the apoptotic cascade, caspase-3 has been described as an important mediator, especially with DNA damage and non-DNA damage stress. Cytokine-mediated stress, however, routes through activation of caspase-8 and caspase-1.35 This raises the possibility of differential caspase activation depending on the environment within the plaque.
The present study demonstrates significant caspase-1 cleavage with plaque rupture when compared with stable plaque. Although cell types are indistinguishable in plaque homogenates, the strong expression of the caspase-1 precursor and its cleavage fragment complements the immunohistochemical localization of caspase-1 in macrophages at plaque rupture sites. The strong evidence of caspase-1 cleavage in the ruptured plaque may stem from the focal and concentrated presence of macrophages undergoing apoptosis. However, the absence of activation of caspase-1 in stable plaques does not rule out the possibility of apoptosis in these lesions but only suggests that the degree of apoptosis is too infrequent to be detected in whole plaque homogenates.
Study Limitations
Plaque rupture is a dynamic process and it is conceivable that an active cell such as macrophage plays an important role in the process. It must be emphasized that acute fatal ruptures are at their morphological endpoint and many of the mechanistic processes leading to the rupture event likely have occurred. Because autopsy material only provides an end-stage specimen, the physiological relevance of the present observations cannot be identified. Furthermore, limitations of autopsy material, including postmortem interval, must also be taken into account. In our study, specimens were often collected more than 8 hours after death, possibly allowing sufficient time for macrophages to undergo apoptosis after rupture was triggered rather than before. The lack of correlation of macrophage apoptosis at rupture sites with postmortem interval, however, argues against apoptosis occurring after the patient’s death. Other published studies in which simulated postmortem delay (up to 15 hours) failed to show increased apoptosis in myocardial and brain tissue corroborate our findings.36,37 Finally, extensive macrophage apoptosis was primarily localized to the rupture site, whereas DNA fragmentation in macrophages in the fibrous cap away from the rupture site and in stable plaques with similar postmortem intervals was significantly less.
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Acknowledgements |
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Footnotes |
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Supported in part by research grants from the American Registry of Pathology and the National Institutes of Health (RO1 HL61799–02).
The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting views of the United States Army, Navy, Air Force, or the Department of Defense.
Accepted for publication July 10, 2000.
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s, macrophages; SMC, smooth muscle cells.