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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:2232-2237.)
© 1997 American Heart Association, Inc.

Articles

Tissue Factor Expression on Macrophages in Coronary Plaques in Patients with Unstable Angina

Koichi Kaikita; Hisao Ogawa; Hirofumi Yasue; Motohiro Takeya; Kiyoshi Takahashi; Taro Saito; Kazuya Hayasaki; Kenji Horiuchi; Akinori Takizawa; Yuichi Kamikubo; ; Shin Nakamura

From the Division of Cardiology, Kumamoto University School of Medicine (K.K., H.O., H.Y.); the Second Department of Pathology, Kumamoto University School of Medicine (M.T., K.T.); Division of Cardiology, Kumamoto Chuo Hospital (T.S.); the Division of Cardiology, Saiseikai Kumamoto Hospital (K.H., K.H.), Kumamoto; the Division of Cardiology, Shizuoka City Hospital (A.T.), Shizuoka; The Chemo-Sero-Therapeutic Research Institute (Y.K.), Kumamoto; and the Department of Molecular and Cellular Biology, Primate Research Institute, Kyoto University (S.N.), Inuyama, Japan.

Correspondence to Hisao Ogawa, MD, Division of Cardiology, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto City 860, Japan. E-mail: ogawah{at}kumamoto-u.ac.jp.

	Abstract

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Abstract Tissue factor is a membrane-bound glycoprotein that functions in the extrinsic pathway of blood coagulation by acting as a cofactor for factor VII, and the resulting complex leads to thrombin production in vivo. The purpose of the present study is to determine whether macrophages express tissue factor in human coronary atherosclerotic plaques. We examined directional coronary atherectomy specimens from 24 patients with unstable angina and 23 with stable exertional angina. In these specimens, macrophages were detected in 22 (92%) of 24 patients with unstable angina versus 12 (52%) of 23 with stable exertional angina (P=.003). The percentage of macrophage infiltration area was significantly larger in patients with unstable angina than in those with stable exertional angina (17±3% versus 6±2%, P=.008). The immunohistochemical double staining revealed the expression of tissue factor on macrophages in 18 (75%) of 24 patients with unstable angina versus 3 (13%) of 23 with stable exertional angina (P<.0001). Thrombus was identified in 20 (83%) of 24 patients with unstable angina versus 12 (52%) of 23 with stable exertional angina (P=.02). Fibrin deposition was mainly observed around macrophages expressing tissue factor in the patients with unstable angina. We have shown that tissue factor expression on macrophages was more frequent in coronary atherosclerotic plaques in patients with unstable angina. Tissue factor expressed on macrophages may play an important role in the thrombogenicity in coronary atherosclerotic plaques of these patients.

Key Words: immunostaining • tissue factor • unstable angina • macrophages • thrombosis

	Introduction

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The most important mechanism underlying the sudden onset of acute coronary syndromes, including unstable angina and acute myocardial infarction, is a plaque rupture of the coronary atherosclerotic plaques followed by the total or subtotal occlusion of the coronary artery caused by the thrombus formation.^{1 2} The thrombus formation after the plaque rupture is a result of activation of platelets and blood coagulation in the coronary atherosclerotic plaques. In fact, the exposure of several components in human atherosclerotic plaques leads to platelet deposition and thrombus formation on the surface.³ The blood coagulation is generally initiated through the action of tissue factor, which is a membrane-bound glycoprotein that functions in the extrinsic pathway of blood coagulation by acting as a cofactor for factor VII, and the resulting complex activates factor IX and X, which leads to the major source of thrombin production in vivo.^{4 5 6} Therefore, the thrombus formation of the coronary artery may be also thought to be initiated through the action of tissue factor in the coronary atherosclerotic lesions.

On the other hand, the plaque rupture is closely implicated in the soft extracellular lipids and macrophages contained in the plaques.^{7 8 9 10} The infiltration area of macrophages in directional coronary atherectomy (DCA) specimens has recently been shown to be larger in patients with acute coronary syndromes than in those with stable angina,¹¹ and the macrophages to be predominant cells at the immediate site of either rupture or superficial erosion of the fibrous cap in patients with acute myocardial infarction.⁸ In vitro study has shown that cultured and activated monocytes expressed high levels of tissue factor antigen in patients with unstable angina,¹² and circulating monocytes also showed increased tissue factor expression in the patients with acute coronary syndromes.¹³ However, it is not clear whether macrophages express tissue factor in human coronary atherosclerotic plaques in patients with unstable angina.

The purpose of the present study is to determine whether macrophages express tissue factor in human coronary atherosclerotic plaques. We examined which cell types express tissue factor in DCA specimens in the patients with unstable angina and in those with stable exertional angina by using an immunohistochemical double staining method.

	Methods

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Patient Population
Included in this study were 47 patients who underwent DCA at our institutions between February 1993 and June 1996 from whom adequate tissue was available. Patients with evidence of 75% or greater narrowing of a major coronary artery and lesion anatomy suitable for DCA were included in the study. The study group of 47 patients was divided into two groups, namely, unstable angina and stable exertional angina groups. The unstable angina group consisted of 24 patients (14 men and 10 women, aged 48-82 years, mean age 67). No patient had secondary unstable angina. Seven patients had at least two episodes of rest pain within 48 hours before DCA, and 8 had postinfarction angina, defined as rest angina within the first 2 weeks after acute myocardial infarction. Seventeen patients received minimal treatments with sublingual nitroglycerin or standard therapy for chronic stable angina, and 7 received maximally tolerated doses of anti-ischemic drugs including intravenous nitroglycerin. The stable exertional angina group consisted of 24 patients (18 men and 5 women, aged 49-82 years, mean age 65) who had typical exertional angina and 90% or greater narrowing of the left or right coronary artery. There were no significant differences between the two groups in the following variables: age, sex, hypertension, smoking, diabetes mellitus, obesity, and serum lipid parameters including total cholesterol, triglyceride, HDL cholesterol, and LDL cholesterol. DCA lesions were located in the left anterior descending coronary artery in 19 patients with unstable angina and in 18 patients with stable exertional angina, in the left circumflex coronary artery in a patient with unstable angina, and in the right coronary artery in 4 and 5 patients, respectively.

Tissue Preparation
The atherectomy specimens were fixed in 10% buffered neutral formalin and embedded in paraffin. Some specimens were fixed in a 2% periodate-lysine-paraformaldehyde fixative for 4 hours, washed with phosphate buffered saline (PBS), and frozen in liquid nitrogen to make frozen sections.

Antibodies
For immunohistochemistry, the following monoclonal antibodies were used: HTF-K108¹⁴ (anti-tissue factor), KP-1 (anti-macrophage, CD68, DAKO, Glostrup, Denmark), HHF35¹⁵ (anti-smooth muscle actin, DAKO), and E8¹⁶ (anti-fibrin, IMMUNOTECH S.A., Marseille).

Immunohistochemistry
Deparaffinized and frozen sections were immunostained using the indirect immunoperoxidase method. After the inhibition of endogenous peroxidase activity according to the method of Isobe et al,¹⁷ the sections were stained with one of the antibodies described above. Then the sections were reacted with peroxidase-labeled antimouse immunoglobulin [F(ab')2] (1:100 dilution; Amersham, Amersham, United Kingdom).¹⁸ Peroxidase activity was visualized using 3,3'-diaminobenzidine (Sigma) as substrate. After immunostaining, the slides were lightly counterstained with hematoxylin. For controls, the tissues were incubated with nonimmunized mouse serum or PBS instead of specific antibodies and were processed by the same procedure. In immunostaining for macrophages, deparaffinized sections were treated in freshly prepared 0.1% trypsin solution at 37°C for 30 minutes and rinsed well in PBS before immunostaining.

Immunohistochemical Double Staining
To identify which cell types express tissue factor, immunohistochemical double staining was performed using the anti-tissue factor (HTF-K108) and one of the antibodies against macrophages (KP-1) or smooth muscle cells (HHF35). In the first step, sections were stained with HTF-K108. After the visualization of peroxidase activity localization with 3,3'-diaminobenzidine as substrate to give a brown color, the sections were rinsed with 0.1 mol/L glycine-HCL buffer (pH 2.2) for 30 minutes to remove the first and second antibodies reacted. In the second step, the same sections were incubated with KP-1 or HHF35 at room temperature for 2 hours. After washing with PBS, the sections were treated with alkaline phosphatase antialkaline phosphatase (APAAP) method using APAAP Kit (DAKO). Alkaline phosphatase activity was visualized using naphthol AS-MX phosphate and fast blue BB salt to give a blue color. To confirm the specificity of the immunoreactivity, control stainings were performed in the same way using nonimmunized mouse serum or PBS instead of specific antibodies in the first or second step or both. Immunostaining was judged independently by two different observers (K.K., M.T.) without knowledge of the clinical status, and the results were given as positive or negative.

Quantification of Macrophage Infiltration
Each section stained with the antihuman panmacrophage monoclonal antibody KP-1 was photographed. The lesions of macrophage infiltration were manually traced in the photographs, and the area was calculated using an NIH-image version 1.55, a public domain image processing and analysis program by Macintosh. Values for macrophage infiltration area and total specimen area are given as mean±SEM and the two-tailed unpaired Student's t test was used in the analysis of each parameter. The chi square test was used to compare the frequency of the positive immunostaining for macrophages, smooth muscle cells, and tissue factor expression, and the frequency of the thrombus in the sections. Probability levels of less than 0.05 were considered to be statistically significant.

	Results

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Most atherectomy specimens were obtained from intima, including atheromatous gruel, sclerotic tissue, and thrombus. Macrophages and smooth muscle cells were mainly found in the sclerotic tissues of the plaques in most specimens. Table 1 shows the frequency of the positive immunostaining for macrophages, smooth muscle cells, and tissue factor expression. Macrophages were detected immunohistochemically in 22 (92%) of 24 patients with unstable angina versus 12 (52%) of 23 with stable exertional angina (P=.003). There was no significant difference in the frequency of the positive immunostaining for smooth muscle cells and tissue factor between the two groups. The thrombus was identified in 20 (83%) of 24 patients with unstable angina versus 12 (52%) of 23 with stable exertional angina (P=.02).

View this table: [in this window] [in a new window]   Table 1. Frequency of Positive Immunostaining for Macrophages, Smooth Muscle Cells, and Tissue Factor

The area of macrophage infiltration in the sections from the patients with unstable angina was larger than that of stable exertional angina (Fig 1A and B). Table 2 shows the percentage of macrophage infiltration area (macrophage infiltration area/total specimen area) in DCA specimens in the two groups. Total area of the sections of each patient in each group was more than 1.0 mm², and the mean values are 3.82±0.28 mm² for each patient with unstable angina and 3.18±0.31 mm² for each patient with stable exertional angina. The percentage of macrophage infiltration area was significantly larger in the patients with unstable angina than in those with stable exertional angina (17±3% versus 6±2%, P=.008).

View larger version (138K): [in this window] [in a new window]   Figure 1. Immunohistochemical staining of DCA specimens. A and B, Staining for macrophages of DCA samples obtained from a 67-year-old man with unstable angina (A), and a 62-year-old woman with stable exertional angina (B). C–H, Double immunohistochemical staining of serial sections from a 62-year-old woman with unstable angina. C and F, Double staining for tissue factor (brown) and macrophages (blue). D and G, Control staining using anti-tissue factor (brown) and non-immune serum (blue). E and H, Control staining using non-immune serum (brown) and anti-macrophages (blue). F–H, Enlargements of the indicated area (rectangles) in C, D, and E, respectively. A and B: x16, bars=625 µm. C–E, x40, bars=250 µm. F–H, x200, bars=50 µm.

View this table: [in this window] [in a new window]   Table 2. Macrophage Infiltration in Directional Coronary Atherectomy Specimens

Tissue factor was observed on both macrophages and smooth muscle cells and was also detected extracellularly in the thrombus. To confirm the cellular localization of tissue factor, immunohistochemical double staining (Fig 1C-H) and consecutive immunostaining using serial sections (Fig 2A-E) were performed. In Fig 1C and F, tissue factor is positive on KP-1 positive macrophages in a section obtained from a patient with unstable angina. The staining pattern of tissue factor in the serial sections (Fig 2A) indicated its localization on the macrophages (compare Fig 2A, B, and D) and smooth muscle cells (compare Fig 2A, C, and E). Table 3 shows the cell types associated with tissue factor expression by immunohistochemical double staining. Tissue factor expression on macrophages was more frequently observed in the group of unstable angina than that of stable exertional angina, via, 18 (75%) of 24 patients with unstable angina versus 3 (13%) of 23 with stable exertional angina (P<.0001). On the other hand, there was no significant difference in the expression on smooth muscle cells between these groups.

View larger version (141K): [in this window] [in a new window]   Figure 2. Immunohistochemical staining for tissue factor (A–C), macrophages (D), smooth muscle actin (E), and fibrin (F and G) of serial sections from a 67-year-old man with unstable angina. B and C, Enlargements of the indicated area in A, showing tissue factor localization around macrophages (B) and smooth muscle cells (C). G, Enlargement of the indicated area in F, showing fibrin deposition around macrophages. A, D, E, F, x40; bars=250 µm. B, C, G, x200; bars=50 µm.

View this table: [in this window] [in a new window]   Table 3. Frequency of Positive Immunostaining for Tissue Factor Expression on Macrophages or Smooth Muscle Cells

To depict the increased thrombogenicity of the DCA specimens in the patients with unstable angina, we examined fibrin deposition in the DCA specimens in the two groups. In addition to expected fibrin deposition in the thrombus in both groups (data not shown), fibrin deposition was also observed around tissue factor-positive macrophages in the patients with unstable angina (Fig 2F and G). On the other hand, the fibrin deposition was not observed around tissue factor–positive smooth muscle cells in both groups (data not shown).

	Discussion

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Tissue factor is a small transmembrane cell surface receptor that mediates cellular initiation of the coagulation serine protease cascades.⁴ In vitro studies have shown that tissue factor expression was observed on various cultured and stimulated cell types such as monocytes,^{12 13 19 20 21 22 23} smooth muscle cells,^{24 25} endothelial cells and fibroblasts.^{25 26} Tissue factor in the media or the adventitial layer of human normal arteries is localized to aid the body in the prevention of blood loss as an initiator of blood coagulation.^{27 28 29 30} Tissue factor has recently been shown to be expressed in human coronary atherosclerotic plaque from DCA specimens.³¹ Therefore, when tissue factor expressed in the coronary atherosclerotic plaques is exposed to the blood by the plaque disruption, it may lead to the thrombus formation and the occlusion of the related coronary artery.

The plaque rupture is closely associated with the soft extracellular lipids,⁷ macrophages,^{8 9 10} matrix-degrading proteases^{9 10 32 33} such as interstitial collagenase (matrix metalloproteinase-1), which degrades two major plaque structural proteins, type I and III collagen, and activated mast cells in the shoulder region of the atherosclerotic plaques.^{34 35} Van der Wal et al⁸ have reported that the macrophages were the predominant cells at the immediate site of either rupture or superficial erosion of the fibrous cap that contained few smooth muscle cells. However, it is not clear whether the macrophages express tissue factor in vulnerable human coronary atherosclerotic plaques in patients with unstable angina.

In the present study, the frequency of macrophage infiltration and the percentage of macrophage infiltration area in DCA specimens were higher in the patients with unstable angina than in those with stable exertional angina. These findings are consistent with the previous report by Moreno et al.¹¹ The frequency of tissue factor–positive macrophages as demonstrated by the immunohistochemical double staining was also higher in the patients with unstable angina than in those with stable exertional angina. The expression of tissue factor on the macrophages seemed to be related to the degree of the macrophage infiltration in the sections. Consequently, the fibrin deposition was mainly observed around massive infiltration of the tissue factor–positive macrophages in the patients with unstable angina and was not observed around tissue factor–positive smooth muscle cells in both groups. Imamura et al¹⁴ have reported that fibrin deposition was restricted to the area around tissue factor–positive macrophages in a model of delayed-type hypersensitivity reaction, suggesting that thrombin activity and fibrin deposition are generated through the activation of blood coagulation initiated by tissue factor on the macrophages. Our present findings also indicate that the tissue factor–positive macrophages rather than the tissue factor–positive smooth muscle cells may be associated with the thrombogenicity in the coronary atherosclerotic plaques in the patients with unstable angina.

The exposure of several components in human atherosclerotic plaques, including collagen and lipids, are considered important in the thrombus formation. Ex vivo studies have demonstrated that the exposure of collagen type I of the vessel wall led to extensive platelet deposition and thrombosis on the surface,³⁶ and that the atheromatous core of human atherosclerotic plaques was associated with the greatest platelet deposition and largest thrombus formation compared with other components of human atherosclerotic lesions.³ Fernández-Ortiz et al³ explained that the thrombogenic properties of the atheromatous core could be attributed to one or more of its constituents, such as the crystaline lipids, soft lipids, phospholipids, or tissue factor.

In several autopsy analyses, asymptomatic coronary disrupted plaques were observed in subjects who died suddenly by noncardiac causes and some patients with diabetes mellitus or hypertension,³⁷ and many patients who died of ischemic heart disease had both thrombosed and nonthrombosed disrupted plaques in their coronary arteries.^{38 39 40} We speculate that the possibility of whether the thrombus is formed or not after the plaque disruption may be closely associated with tissue factor contained in the preexisting coronary atherosclerotic lesion.

In conclusion, by using the immunohistochemical double staining method we have shown that the expression of tissue factor on macrophages was more frequent in the coronary atherosclerotic plaques in the patients with unstable angina. The present findings suggest that tissue factor expressed on the macrophages plays an important role in the thrombogenicity in the coronary atherosclerotic plaques of these patients.

	Acknowledgments

 
This study was supported in part by grant-in-aid for scientific research C07670794 from the Ministry of Education, Smoking Research Foundation Grant for Biomedical Research, Tokyo, and a grant from Japan Cardiovascular Research Foundation, Osaka, Japan. The authors thank Takahisa Imamura, Division of Molecular Pathology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan, for his advice on our study.

Received December 31, 1996; accepted April 23, 1997.

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