CLINICAL RESEARCH: ATHEROSCLEROSIS
Cellular Immunostaining of Angiotensin-Converting Enzyme in Human Coronary Atherosclerotic Plaques
Flavio Ribichini, MD*,*,
Francesco Pugno, MD ,
Valeria Ferrero, MD*,
Gianni Bussolati, MD, FRCPath ,
Mauro Feola, MD,
Paolo Russo, MD ,
Carlo Di Mario, MD||,
Antonio Colombo, MD|| and
Corrado Vassanelli, MD*
* Catheterization Laboratory, Ospedale Maggiore della Carità, Universita’ del Piemonte Orientale, Novara, Italy
Ospedale Santa Croce e Carle, Cuneo, Italy
Dipartimento di Scienze Biomediche dell’Universita’ di Torino, Torino, Italy
Clinica Villa Maria Pia, Torino, Italy
|| Centro Cuore Columbus, Ospedale San Raffaele, Milano, Italy
Manuscript received May 31, 2005;
revised manuscript received August 30, 2005,
accepted September 8, 2005.
* Reprint requests and correspondence: Dr. Flavio Ribichini, Director Catheterization Laboratory, Università del Piemonte Orientale, Ospedale Maggiore della Carità, Corso Mazzini 18, 28100 Novara, Italy. (Email: flavio.ribichini{at}med.unipmn.it).
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Abstract
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OBJECTIVES: The aim of this study was to determine the cellular localization of angiotensin I-converting enzyme (ACE) in the atherosclerotic plaque and its correlation with inflammation and cellular proliferation.
BACKGROUND: Angiotensin I-converting enzyme inhibitors reduce the incidence of vascular events; therefore, tissue ACE may play a determinant role in the pathophysiology of the atherosclerotic plaque.
METHODS: Histology and immunocytochemistry of de novo coronary plaques retrieved with directional coronary atherectomy from 141 patients were analyzed: 87 with stable angina, 39 with subacute unstable angina, and 15 with acute unstable angina.
RESULTS: Compared with stable patients, unstable patients showed more thrombotic lesions (72% vs. 27%, p < 0.0001), smaller areas of fibrous plaque (2.3 ± 1.2 mm2 vs. 2.8 ± 1.1 mm2, p = 0.02), higher cellular proliferative score (0.78 ± 0.9 vs. 0.27 ± 0.6, p = 0.003), larger content of ACE-stained cells (26.3 ± 23% vs. 12.6 ± 15%, p = 0.005) and larger areas of inflammation as identified by CD68 immunostaining (29.5 ± 22% vs. 20.2 ± 19%, p = 0.02). A significant linear correlation was found between CD68- and ACE-stained areas (mm2) among unstable patients (r = 0.6, p = 0.0001), but it was absent among stable patients (r = 0.006, p = 0.9). Co-localization of ACE, CD68, and alpha-actin was confirmed by double immunostaining. Patients with Ki-67–positive staining as an index of cell proliferation showed also significantly larger areas of ACE immunoactivity (p = 0.004).
CONCLUSIONS: Our data demonstrate ACE immunoactivity in inflammatory and proliferative cells of coronary atherosclerotic plaques. In particular, patients with unstable angina showed larger areas of ACE immunoactive tissue and proliferating cells compared with stable patients. These observations support a role of the enzyme in the pathophysiology of coronary unstable plaques and suggest potentially different effects of ACE inhibitors according to clinical presentation.
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Abbreviations and Acronyms
| | ACE = angiotensin I-converting enzyme | | ACS = acute coronary syndromes | | DCA = directional coronary atherectomy | | HPF = high-power fields | | ID = insertion/deletion | | MI = myocardial infarction | | SMC = smooth muscle cells |
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Angiotensin I-converting enzyme (ACE) inhibitors cause a significant reduction in mortality, recurrence of acute myocardial infarction (MI), new episodes of unstable angina, and need for new coronary revascularization procedures in patients with left ventricular dysfunction (1). Many of these initial observations have been confirmed also in patients at high risk for vascular events and normally functioning hearts treated with ramipril in the Heart Outcomes Prevention Evaluation (HOPE) trial (2). In a lower-risk population with stable coronary heart disease, perindopril reduced the occurrence of death and MI, but did not prevent episodes of unstable angina or the need for myocardial revascularization in the European Trial on Reduction of Cardiac Events With Perindopril on Stable Coronary Artery Disease (EUROPA) (3). In the most recent Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) trial, trandolapril did not reduce clinical events in patients with stable coronary heart disease and preserved left ventricular function (4). Explanations for the discrepancies among these trials remain merely speculative; they may derive from the different use of concomitant treatments, or rather be due to a lower basal extent of activation of the renin-angiotensin system in stable patients with preserved left ventricular function (5).
In the normal heart, tissue ACE seems not to be required for normal heart development, and angiotensin II is not necessary for normal cardiac function (6). Conversely, any kind of injury to the heart results in marked ACE induction; in particular inflammation causes accumulation of angiotensin II as macrophages over-express ACE in interstitial sites (6,7). Angiotensin II contributes to the initiation and progression of atherosclerosis by increasing oxidative stress, enhancing the adrenergic state, stimulating plasminogen activator inhibitor-1 production, and increasing platelet aggregation (1,5–7). Conversely, the reduction of angiotensin II and the preservation of bradykinin and nitric oxide production that derives from the inhibition of the ACE may account for the vascular protection provided by these drugs. Therefore, ACE activity in the coronary atherosclerotic plaque is likely to be a pathophysiologic substratum for the clinical benefits of ACE inhibition.
Previous studies have described the cellular composition of atherosclerotic plaques that cause stable or unstable coronary syndromes (8). Diet et al. demonstrated the presence of ACE in human atherosclerotic coronary arteries by means of immunostaining (9), and increased tissue ACE activity in plaques of patients with acute coronary syndromes (ACS) has been reported (10).
Plasma ACE level is under genetic control, and the insertion/deletion (ID) polymorphism of the ACE gene is a marker of the ACE activity (11). The relationship between ID polymorphism, plasma ACE, and tissue ACE is not fully defined.
We hypothesized that the ACE present in the plaque could be involved with mechanisms that rule the patient’s clinical outcome because of its existence in inflammatory cells of vulnerable plaques that may cause clinical events. Therefore, we analyzed specially stained histology sections of coronary atherectomy samples retrieved from patients with well characterized stable or unstable angina to determine if the intracellular enzyme was co-localized with cellular markers of inflammation and cell proliferation. Furthermore, the ID polymorphism of the ACE gene and the serum levels of the enzyme were also determined in non–ACE-inhibited patients and correlated to tissue ACE staining.
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Methods
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Patient population.
A total of 141 directional coronary atherectomy (DCA) specimens obtained from native coronary arteries were analyzed. Each one corresponds to a single "de novo" lesion per patient, responsible for the clinical presentation (culprit lesion). All patients had stable angina or silent ischemia, or unstable angina classified according to Braunwald’s definition (12), and all gave informed consent to undergo DCA. The study protocol was approved by each of the relevant institutions where the DCA procedures were performed.
The DCA specimens were obtained after multiple cuts and immediately immersed in 4% buffered formalin. Samples were processed for paraffin embedding according to conventional techniques to perform hematoxylin-eosin and immunocytochemistry staining.
Hematoxylin-eosin histology.
The total and segmental area for each plaque sample and areas of each cellular components were quantified by accurate computer-aided planimetry of each specimen using an acquisition program Image Pro Plus (software version 4.0, Media Cybernetics, Silver Spring, Maryland). The characteristics of each coronary plaque were classified as being atheroma (necrotic cores and cholesterol clefts without connective tissue matrix) or fibrocellular, graded as paucicellular or fibrotic (<30 spindled cells in high-power fields [HPF]), moderately cellular (30 to 100 spindled cells in HPF), and hypercellular (>100 spindled cells in HPF). Thrombi and calcium were also analyzed qualitatively and as a percent of the surface of the plaque area. Thus, plaque material from each patient could contain up to six different histologic characteristics. All classifications and measurements were performed blindly of the clinical presentation.
Antibody staining.
Immunostaining for the detection of smooth muscle cells (SMC), macrophages, cells containing ACE and proliferation marker Ki-67 were performed in samples from all patients. Respectively, sections were stained with 0.66 µg/ml anti-SMC (anti-human alpha-smooth muscle actin clone 1A4 [M 851; DAKO, Milan, Italy]); 0.1 µg/ml anti-CD68 (anti-human macrophage antibody clone KP-1 [M814; DAKO]); 10 µg/ml ACE (anti-human ACE [BMA]; Biomedical AG, Augst, Switzerland); and cell proliferation was determined with anti-human Ki-67 antibody diluted 1:400 (clone MIB-1; Immunotech, Marseille, France). Positive controls were tested using normal human tissues of smooth muscle (normal colon) for alpha-actin, spleen for KP-1, lung for ACE, and lymphoid tissue for Ki-67. The degree of cellular proliferation was assessed on the Ki-67–stained sections according to the graded MIB score (0 to 3) proposed by Flugelman et al. (13).
Double immunostaining.
To identify cell types corresponding to ACE-positive elements, we proceeded with a sequence of immunocytochemical reactions performed in the same section using non–cross-reacting antibodies from different species, as described elsewhere (5,9), to identify cells containing ACE and CD68 and cells containing ACE and alpha-smooth muscle actin.
The ID polymorphism of the ACE gene was determined by polymerase chain reaction using 500 ng of genomic deoxyribonucleic acid extracted from white blood cells as previously detailed (11). Serum ACE levels were measured using fluoril-acrioil-phenilalanilglycilglycina substratum (SIGMA, St. Louis, Missouri), as detailed in the same previous work.
Statistical analysis.
Continuous data are expressed as means and standard deviations; discrete variables are given as absolute values and percentages. Two-tailed Student t test was used for comparison of parametric variables and the chi-square or exact test for discrete variables. A linear regression analysis was used to correlate areas stained for ACE and inflammation (ACE and CD68 staining in mm2). A probability value of less than or equal to 5% was considered significant.
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Results
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Baseline clinical data of the 141 patients are reported in Tables 1 and 2. Patients with unstable angina were more frequently females, smokers, and were under ACE inhibitor treatment at the time of DCA. In most cases (70%), ACE inhibitors were started at hospital admission.
Plasma ACE levels and tissue ACE staining.
At the time of DCA, 38 patients were under ACE inhibitor treatment. Plasma ACE level was available in 95 of the 103 non–ACE-inhibited patients, and the ID ACE genotype in 85. As expected, plasma ACE levels were higher in deletion/deletion (DD) patients (41.8 ± 17 U/l, n = 17), intermediate in ID patients (22 ± 10 U/l, n = 52), and lower in insertion/insertion (II) patients (11.3 ± 3 U/l, n = 16), p < 0.001. In this population of non–ACE-inhibited patients, plasma ACE concentrations (U/l) did not correlate with the surface of ACE-stained cells (mm2): r = 0.02, p = 0.5, whereas there was a significant correlation in the subgroup of non–ACE-inhibited patients with unstable angina: r = 0.65, p = 0.02. Tissue ACE staining was different according to the ID polymorphism: DD patients showed larger areas of ACE-stained cells (14 ± 21%) compared with ID (10.6 ± 13%) and II (5 ± 9%), respectively, p < 0.05 for DD versus ID, and DD versus II. Such difference was more pronounced in patients with unstable angina (DD: 28 ± 15%, ID: 12 ± 8%, II: 2 ± 7%, p < 0.05 for DD vs. ID, and DD vs. II).
Histology.
The comparison of the histologic features observed between patients divided as having stable (n = 87) or unstable angina (n = 54) shows that in unstable patients the presence of thrombus was more frequent (39 patients = 72% vs. 23 patients = 26%, p < 0.0001), and plaque type was predominantly hypercellular. The presence of calcium in the plaques (25 = 29% vs. 12 = 22%, p = 0.3) or atheromatous gruel (17 = 20% vs. 14 = 26%, p = 0.5) was similar in the two groups. Detailed morphometric data expressed in mm2 and percent of the plaque surface are disclosed in Table 3.
For further analysis of the histologic findings, patients with unstable angina were classified as having acute unstable angina (chest pain at rest in the last 48 h: 15 patients) or subacute unstable angina (asymptomatic for at least 48 h before DCA: 39 patients) (Table 4). Acute unstable patients showed significantly less fibrotic tissue and some larger amounts of thrombus (Table 4). In predominantly fibrous plaques, some lymphocytes and very few plasma cells, other than SMC and macrophages, were observed in the fibrous matrix. In moderately or highly cellular plaques, inflammatory and spindled-shaped cells were the predominant types. In plaques containing atheroma, rare giant cells were present next to the cholesterol clefts. Endothelial cells were present in neovessels of all types of plaque and in fragments of intact intima.
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Table 4. Histologic Morphology and Immunocytochemistry According to Clinical Presentation; Unstable Angina Is Analyzed in Acute or Subacute Subgroups
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Immunocytochemistry.
The immunocytochemistry study revealed that unstable patients had a significantly higher proliferative score, larger content of ACE-stained cells, and larger areas of inflammation characterized by CD68 immunostaining (Table 3). In patients with acute unstable angina, areas occupied by cells staining for ACE were larger and areas of inflammation marker CD-68 tended to be also larger compared with subacute unstable patients (Table 4).
The vast majority of ACE-positive cells were observed in areas of clustered cells also positive for inflammation CD68 immunostaining in most cases. This finding was confirmed by co-localization of ACE and CD68 antigen in fragments analyzed by means of double immunostaining (Fig. 1). By linear regression analysis, a significant association was found between the area (mm2) occupied by macrophages (identified by CD68 immunostaining) and ACE-reactive areas in patients with unstable angina: r = 0.6, p = 0.0001. In tissue of patients with stable angina, such correlation was absent: r = 0.006, p = 0.9 (Fig. 2).
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Figure 1 Double immunostaining of coronary plaque tissue from a 65-year-old man with subacute unstable angina. (A) Immunohistochemical staining (red reaction product) using anti–angiotensin I-converting enzyme antibodies and an immuno-alkaline phosphatase reaction that identifies as angiotension I-converting enzyme-positive cells the endothelium and numerous stromal cells, arranged in clusters or isolated in the stroma. (B) After removal of the red reaction product, the same area is stained in brown with an immunoperoxidase reaction revealing CD68-positive macrophages. Comparison of the two figures reveals also that some strongly angiotensin I-converting enzyme-positive cells do not correspond to macrophages.
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Figure 2 Linear regression of the association of macrophage area (mm2) identified by CD68 immunostaining and area of angiotensin I-converting enzyme-stained cells (mm2) in patients with stable angina (A) or unstable angina (B), showing both positive reactions. (A) r = 0.006, p = 0.9; (B) r = 0.6, p = 0.0001.
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The content of ACE-stained cells observed in patients showing areas of proliferating cells (Ki-67–positive staining and MIB score  1) was significantly larger than that of patients without signs of cell proliferation, i.e. MIB score = 0 (30.3 ± 20% vs. 14.5 ± 19%, p = 0.004). Immunostaining and cell quantification demonstrated that 90% of the Ki-67–positive proliferating cells co-localized with CD68 antigen-stained cells in identical sections, indicating their inflammatory nature. The remaining 10% showed a spindled shape and co-localized with alpha-actin–stained cells, indicating the smooth muscle nature.
In areas of ACE-positive staining not associated to inflammatory immunoreactivity, two different cell types were identified: endothelial cells of neovessels (Fig. 3) and spindled-shaped cells of the neointima. Double immunostaining of such spindled cells with anti-ACE and anti-alpha-actin antibodies demonstrated that approximately 15% of alpha-actin–positive spindled cells were also ACE-positive in the same sections, suggesting their SMC nature (Fig. 4). The quantitative distribution of these cells was not different among the three clinical groups.
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Figure 3 Immunoreaction with angiotensin I-converting enzyme antibody showing positive staining of the endothelial cells of neovessels of the neointima (arrows).
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Figure 4 Double immunostaining of coronary plaque tissue from a 71-year-old woman with subacute unstable angina stained in sequence as in Figure 1. Immunohistochemical procedure for angiotensin I-converting enzyme (A: red color) and alpha-actin (B: brown color). Comparison of the two figures demonstrates that some actin-positive cells of the smooth muscle cell type are also angiotensin I-converting enzyme-positive.
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Discussion
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Cellular ACE in atherosclerotic plaques correlates with inflammatory cells, cellular proliferation, and unstable clinical presentation. Furthermore, the ID polymorphism of the ACE gene correlates with the tissue ACE immunostaining in unstable patients.
In our study, areas occupied by macrophages were significantly associated with ACE-stained areas in unstable patients but not in stable patients (Fig. 2). This observation is consistent with the augmented expression of the enzyme secondary to macrophage activation expected in ACS (9,14,15). Furthermore, larger areas of ACE immunoactivity were found in sections showing Ki-67–positive staining, suggesting that cell proliferation in the plaque may be associated with the enhanced availability of angiotensin II that derives from local ACE activity, an interesting mechanism previously reported in primates and in humans by others (16).
Macrophages are known to up-regulate ACE activity up to 100-fold in vitro during differentiation (15); furthermore, the co-localization of ACE, angiotensin II, and the type 1 receptor for angiotensin II with macrophages at the site of rupture of coronary atherosclerotic plaques in patients with ACS reinforces the hypothesis of a role of ACE in plaque instability and the occurrence of clinical events (17). The beneficial anti-atherosclerotic properties of ACE inhibitors, found to be independent of the blood pressure reduction, may be at least in part due to the attenuation of the local effects induced by ACE and their destabilizing actions at the tissue plaque level (1,2).
Other ACE immunoreactive cells not related to macrophages were endothelial cells of neovessels (Fig. 3) and spindled-shaped cells that showed alpha-actin immunoactivity at double staining (Fig. 4), suggesting a role of the enzyme in the neovascularization of the atherosclerotic plaque, and possibly in the transformation of SMC-like cells from a dedifferentiated to a differentiated phenotypic state or from other types of cells such as infiltrating macrophages or fibroblasts, as has been previously proposed by other authors who analyzed sections of vessel wall from autopsy specimens (14,15).
ACE inhibitors reduce plasma ACE levels independently of the patient’s ID genotype (18), and preliminary observations suggest that they may also attenuate plaque tissue ACE immunostaining (5,19). However, the effectiveness of ACE inhibitors in the atherosclerotic plaque given at conventional doses is unknown. Robust clinical data support the efficacy of these drugs in reducing the incidence of major clinical events (death and MI), and minor events (angina and need for revascularization) in patients with severe morbidity such as in survivors of a MI, patients with heart failure (1), or patients at high risk for vascular events (2,5). More recent investigations indicate that ACE inhibitors may exert fewer clinical benefits in less critical patients as those with stable coronary heart disease and preserved left ventricular function under conventional treatment (4). A speculative interpretation for such observation could be that of a different cellular substrate at the plaque level for ACE inhibitors according to the clinical presentation of the patient, with significantly less ACE immunoactivity in stable patients, as is suggested by our findings. The benefits of ACE inhibitors may therefore be more consistent in the context of an overexpression of the renin-angiotensin system as, for example, in patients with a recent MI, heart failure, or ACS.
Study limitations.
Directional coronary atherectomy causes compression of some of the tissue as material is cut and extracted from the lumen side of the lesions, which normally accounts for one-third of the total plaque, and this may not reflect total plaque composition. Furthermore, the role of cells mainly present in the media or the adventitia cannot be assessed.
Conclusions.
The cellular localization of ACE in areas of inflammation occupied by macrophages as well as in areas with proliferating cells supports a causative role of the enzyme in the pathophysiology of ACS. The differences regarding tissue ACE immunoactivity in stable and unstable patients may account for potentially different effects of ACE-inhibitor drugs according to clinical presentation.
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References
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Abstract
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