© 1996 American Heart Association, Inc.
Articles |
Interleukin-1ß in Coronary Arteries of Patients With Ischemic Heart Disease
the Sections of Cardiac Surgery (J.G., J.A., P.G., C.M.H.), Cardiology (S.E.F.), and Molecular Medicine (H.H.), University of Sheffield (UK).
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Abstract |
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Interleukin-1ß (IL-1ß ) is known to have a number of effects on the different cell types present within coronary arteries. In this study we identified the location and phenotype of cells containing IL-1ß in human coronary artery specimens from patients suffering from either coronary atherosclerosis or cardiomyopathy and correlated the presence of IL-1ß with disease severity. Luminal endothelial cells, adventitial vessel wall cells, and macrophages were double labeled immunohistochemically for IL-1ß protein and a cell type–specific monoclonal antibody for either endothelial cells or macrophages. In situ hybridization was performed to locate the presence of IL-1ß mRNA within the coronary artery wall. In this study IL-1ß protein was found to be increased in the adventitial vessel walls of atherosclerotic coronary arteries compared with coronary arteries from nonischemic cardiomyopathic hearts. This increase was directly proportional to the severity of coronary atherosclerosis. IL-1ß protein was also detected in luminal endothelium and macrophages of atherosclerotic coronary arteries and coronary arteries from nonischemic cardiomyopathic hearts. IL-1ß mRNA was found in luminal endothelial cells, adventitial vessel endothelial cells, and macrophages. We conclude that IL-1ß is produced by endothelial cells and macrophages in coronary arteries from ischemic hearts and to a lesser extent from nonischemic cardiomyopathic hearts.
Key Words: atherosclerosis • interleukin-1ß • coronary artery
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Introduction |
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Interleukin-1 forms part of a complex integrated group of cytokines that has been shown to mediate the inflammatory host response to infection and injury.1 2 3 4 It has also been implicated in the pathophysiology of endotoxin- and immune-mediated shock.5 6 In vitro evidence suggests that this cytokine may act as a regulatory protein in the atherosclerotic process. Several mechanisms have been suggested, including regulation of VSMC mitogenesis,7 8 9 10 stimulation of leukocyte adherence to the endothelium,11 12 13 modulation of LDL metabolism,14 15 16 induction of extracellular matrix proteins by endothelium,17 and promotion of vascular permeability.18 Other studies have demonstrated that IL-1 suppresses vascular contractility19 and has procoagulant activity.20 21 In 1989, Wang et al22 detected increased levels of IL-1
and IL-1ß mRNAs in human atherosclerotic plaque using RT-PCR, suggesting that the protein is synthesized locally. In addition, Tipping and Hancock23 have shown IL-1 protein in isolated, cultured human atheromatous macrophages from the carotid arteries. Furthermore, IL-1ß mRNA and protein have been demonstrated in the endothelium, VSMCs, and macrophages of atherosclerotic arteries from nonhuman primates.24 25 However, its location and cellular source in human coronary arteries have not previously been investigated. The aims of this study were to identify the location and phenotype of cells containing IL-1ß in human coronary artery specimens from patients suffering from coronary atherosclerosis and cardiomyopathy and to correlate the presence of IL-1ß with disease severity. This was done with the use of double immunolabeling for IL-1ß together with endothelial cell and macrophage markers. Furthermore, expression of IL-1ß mRNA was determined by in situ hybridization histochemistry.
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Methods |
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Tissue Samples
The explanted hearts of 18 transplant recipients suffering from ischemic cardiac disease (n=13, 12 men) or nonischemic cardiomyopathy (n=5, 4 men) were collected from the operating theater at the time of transplantation and transferred to the laboratory within minutes after removal of the heart. At the time of transplantation, patients with ischemic heart disease were on diuretics (92% of patients), angiotensin-converting enzyme inhibitors (85%), warfarin (69%), nitrates (38%), aspirin (31%), and digoxin (31%). Patients suffering from nonischemic cardiomyopathy were on diuretics (100%), angiotensin-converting enzyme inhibitors (100%), warfarin (80%), nitrates (80%), and digoxin (80%). The coronary ostia were cannulated and the coronary arteries perfused with ice-cold isotonic saline solution, administered through a gravity feed, to clear any blood. The coronary arteries were then dissected free by a "no-touch technique" as described by Gottlob,26 cut into 5-mm segments, and immediately frozen in liquid nitrogen for immunohistochemistry and in situ hybridization histochemistry. All specimens were frozen within 30 minutes of explantation of the heart. Further specimens were fixed in buffered formalin and subsequently processed and paraffin embedded for routine analysis of sections stained with hematoxylin and eosin and Miller's elastic van Gieson's stain. Additional frozen sections were prepared for in situ hybridization histochemistry. The pathological diagnosis of the diseased explanted heart was determined by an experienced cardiac pathologist.
Segments of human left internal mammary artery and long saphenous vein obtained at the time of coronary artery bypass surgery were used as control, nondiseased vascular tissue.
Immunostaining for IL-1ß
IL-1ß immunostaining was performed on cold processed plastic sections of coronary artery since this provided both good morphology and retention of IL-1ß epitope, which was not possible with frozen or formalin-fixed paraffin sections. Segments of artery were fixed overnight in acetone containing 2 mmol/L phenylmethylsulfonyl fluoride and 20 mmol/L iodocetamide. The next day, specimens were placed into fresh acetone, then dehydrated in methyl benzoate. Specimens were embedded in glycol methacrylate (JB4 resin, Park Scientific) at 4°C, and 3-µm sections were cut on an autocut microtome (Reichert-Yung) fitted with a tungsten carbide knife and collected onto aminopropyltriethoxysilane-coated (Sigma Chemical Co) slides. After removal of endogenous peroxidase with 2% hydrogen peroxide, dried sections were incubated overnight at room temperature with a mouse monoclonal antibody to IL-1ß (Genzyme Corp) at a final concentration of 12 µg/mL, diluted with PBS containing 10% horse serum. This antibody recognizes both the full length and one processed form of the IL-1ß protein as determined by Western blotting (data not shown). Sections were then washed three times in Tris-buffered saline containing 2% horse serum. Biotinylated horse anti-mouse secondary antiserum (Vector) was then applied, followed by StrepABComplex/HRP (Dako). Finally, antibody binding was visualized with DAB and counterstained with Mayer's hematoxylin.
Double Immunostaining for IL-1ß and Endothelial Cells or Macrophages
Double immunostaining was performed to identify the phenotype of cells containing IL-1ß. IL-1ß staining was performed as above, but after incubation with DAB, slides were incubated for 2 hours in elution buffer consisting of 0.2 mol/L glycine/hydrochloric acid (pH 2.2) to remove any excess antibody from the first reaction. Slides were then incubated overnight with either a mouse monoclonal antibody to von Willebrand factor antigen (Dako) to stain endothelial cells or an antibody to CD-68 (KP-1, Dako) to stain macrophages. The next day the sections were incubated with rabbit anti-mouse antibody (Dako) followed by alkaline phosphatase/anti–alkaline phosphatase (Dako), then new fuchsin substrate system (Dako) and levamisole. Finally, sections were counterstained with Mayer's hematoxylin and mounted with Crystal/Mount (Biomeda Corp).
Immunohistochemistry Controls
For all immunohistochemistry experiments, negative controls were performed. These consisted of sections incubated with nonimmune mouse IgG at concentrations similar to those of the primary antibody, as well as sections without primary or secondary antibody, for both the first and second antibodies in double-labeling experiments. In addition, immunostaining for IL-1ß was performed on segments of left internal mammary artery and long saphenous vein.
Examination and Analysis of Histological Sections
All histology sections were examined under light microscopy by one of the authors (J.G.), who was unaware of the pathological diagnosis of the explanted heart. Twelve random sections were reexamined by the same author and C.M.H. to determine reproducibility. In addition, replicate sections were cut from eight blocks to determine reproducibility.
The entire histological specimen of every slide was examined. The number of luminal endothelial cells, macrophages, and adventitial vessels was estimated, and those that were positively stained were graded arbitrarily from 0 to +++, as follows: 0, no stained cells or vessels; +, up to one fifth of the cells or adventitial vessels stained; ++, from one fifth to one half of cells and vessels stained; and +++, more than half of cells and vessels stained. The degree of atherosclerosis was also classified into four severity grades, as follows: (1) absent: very little or no intimal thickening; (2) mild: more extensive intimal thickening; (3) moderate: plaque without calcification; and (4) severe: calcified plaque.
In Situ Hybridization Histochemistry
IL-1ß mRNA was detected and localized in situ on frozen sections of artery with an oligonucleotide probe cocktail (R&D Systems). The specificity of each of the oligonucleotide probes (exons 5, 6, and 7) was verified by Northern blots. Each oligonucleotide hybridized separately to a single 1.6-kb mRNA species, identical to that of IL-1ß (data not shown).
Serial 6-µm frozen tissue sections of coronary artery from seven patients (five with ischemic heart disease and two with nonischemic cardiomyopathy) were randomly selected for in situ hybridization study. The sections were cut onto APES-coated RNase-free slides and fixed in 4% fresh paraformaldehyde at room temperature for 20 minutes. The tissue samples were denatured in 2x SSC at 70°C for 30 minutes, digested with proteinase K (2 to 5 µg/mL), and prehybridized for 1 hour at 37°C in 50% formamide, 10% wt/vol dextran sulfate, 5x Denhardt's solution, and 0.6 mol/L NaCl. The biotinylated probe cocktail was applied to the tissue sections at 800 ng/mL in hybridization solution. Stringent controls in addition to validation of the probe by Northern blot were used: (1) biotinylated oligo(dT) (positive control); (2) no proteinase K, preventing access of the probe to the target (negative control); (3) insulin oligonucleotide probe (negative control); (4) hybridization solution without probe (negative control); and (5) pretreatment of tissue with 200 µg/mL RNase A in 10 mmol/L Tris-HCl (pH 8.0), 1 mmol/L EDTA, and 500 mmol/L NaCl for 30 minutes at 37°C, followed by incubation with the probe (negative control).
After an 18-hour hybridization at 37°C, the tissues were washed at 37°C, twice in 4x SSC for 10 minutes, twice in 2x SSC for 10 minutes, and twice in 0.2x SSC for 10 minutes. Tissues were then incubated at 24°C for 30 minutes with a mouse monoclonal anti-biotin antibody (1:100 dilution, Dako), followed by a rabbit anti-mouse peroxidase-conjugated secondary antibody (RAMPO systems, Dako), and the reaction was developed with the use of DAB (Sigma Chemical Co) in 0.1 mol/L Tris, pH 7.2. Nuclei were counterstained with Harris hematoxylin.
Statistical Analysis
Statistical analysis was performed by the Sheffield Statistical Service Unit, University of Sheffield (UK), using a Statistical Analysis System software package, version 6.08. Association between the estimated amount of IL-1ß and the extent of atherosclerotic disease was calculated with a modification of Fisher's exact test (two tailed).27 This test was also used to analyze the difference between the presence of IL-1ß in ischemic heart disease and cardiomyopathy. Values of P<.05 were considered significant. The 
statistic was used to determine interobserver and intraobserver agreement.
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Results |
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The conventional histological evidence of coronary artery atherosclerosis ranged from no disease in one of the nonischemic cardiomyopathy explanted hearts to fatty streaks and advanced calcified plaques in patients with ischemic heart disease. The histopathological diagnoses of the nonischemic cardiomyopathic hearts were constrictive (2), hypertrophic (1), postviral (1), and idiopathic (1) cardiomyopathy. Intimal hyperplasia was present in 4 of these patients. The mean age of both patient groups was not significantly different: patients with ischemic heart disease, 50.9 years (range, 33 to 71 years; median, 52 years) and patients with nonischemic cardiomyopathy, 49.2 years (range, 25 to 60 years; median, 57 years). The segments of coronary arteries studied were 8 right coronary arteries, 7 left anterior descending arteries, and 3 circumflex coronary arteries. All sections were evaluated for the presence of IL-1ß protein, and its location was investigated by double staining of luminal and adventitial vessel endothelial cells with an antibody to von Willebrand factor antigen and of macrophages with an antibody to CD-68 (KP-1). The presence of mRNA for IL-lß in arterial wall cells was studied by in situ hybridization histochemistry in 7 of these patients. To determine the reproducibility of the histological grading, eight blocks had multiple sections cut. Analysis of these slides showed good agreement (
=.715). In addition, good agreement was also found between two independent observers (=.722).
IL-1ß protein was observed in the luminal endothelium (Figure
, panel A) in all 13 atherosclerotic coronary arteries from hearts explanted from patients with ischemic heart disease and in 4 of 5 coronary arteries from nonischemic cardiomyopathic hearts. These 4 coronary arteries showed intimal hyperplasia, although ischemia was not the cause for the failing heart. IL-1ß protein was detected in the adventitial vessel endothelium in 12 of 12 specimens from patients with ischemic heart disease and in 2 of 5 specimens from patients with nonischemic cardiomyopathy. This difference is statistically significant (P=.015, two-tailed Fisher's exact test). Furthermore, the adventitial capillaries appeared more dense with the severity of atherosclerotic disease in the coronary arteries. IL-1ß was present in macrophages (mainly foam cells) of 10 of 11 specimens of coronary arteries from ischemic hearts and in 3 of 5 specimens from nonischemic cardiomyopathic hearts. The degree of staining observed ranged from none (0) to more than half of cells stained for IL-1ß (+++) (Table 1). There was very little positive staining for IL-1ß protein in VSMCs.
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Detection and Localization of IL-1ß Protein in Atherosclerotic Coronary Arteries
The most common cells harboring IL-1ß protein were adventitial capillary endothelial cells (Figure
, panel B) in ischemic hearts. These cells were double immunostained for von Willebrand factor antigen to confirm their endothelial phenotype (Figure, panel C). This antibody was also used with IL-1ß antibody to double stain luminal endothelial cells. The luminal endothelium adjacent to a plaque or intimal thickening expressed minimal amounts of IL-1ß protein; however, the adventitia adjacent to plaque and intimal thickening frequently but not consistently contained an increase in adventitial capillary expression of this cytokine. A proportion of macrophages in the intima (mainly lipid-laden cells or foam cells) stained for IL-1ß protein and KP-1 (Figure, panel D). IL-1ß protein was also detected in a proportion of KP-1–positive adventitial macrophages. However, the majority of macrophages did not stain positive for IL-1ß (Figure, panel E). Little IL-1ß was detected in VSMCs.
The extent of coronary atherosclerosis in patients with ischemic heart disease was related to the extent of IL-1ß immunoreactivity in luminal endothelium, adventitial capillary cells, and macrophages (Table 2). Two-tailed Fisher's exact test was applied, and a statistically significant positive association was found between severity of atherosclerosis and IL-1ß protein in adventitial capillaries (P=.006).
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Detection and Localization of IL-1ß Protein in Coronary Arteries From Nonischemic Cardiomyopathic Hearts
IL-1ß protein was less common in luminal and adventitial capillary endothelial cells and macrophages in coronary arteries from nonischemic cardiomyopathic hearts compared with arteries from ischemic hearts (Table 1). The amount of protein present in these cells was less than that detected in arteries from ischemic hearts. This difference in amount of protein detected between the ischemic and the nonischemic hearts only reached statistical significance in the adventitial vessel wall subgroup.
The endothelium was intact in coronary artery sections from patients with nonischemic cardiomyopathy as detected by immunostaining for von Willebrand factor antigen. However, only a few of these endothelial cells stained positive for IL-1ß protein. Sparse macrophages were present in the adventitia and the media as determined by positive staining for KP-1, and only a small proportion of these stained for IL-1ß protein.
Detection and Localization of IL-1ß Protein in the Left Internal Mammary Artery and Long Saphenous Vein
IL-1ß was not detected in sections from these vessels (Figure, panel F). Adventitial vessels and luminal endothelium were detected in both saphenous veins and internal mammary arteries, but these did not contain IL-1ß protein. Occasional macrophages were detected in long saphenous vein sections but none in the internal mammary artery; however, these also did not contain IL-1ß.
Detection and Localization of IL-1ß mRNA in Human Coronary Artery
Seven coronary artery sections were selected from the same group of patients used for double staining to provide a representation of the range of the diseased hearts; five samples were taken from ischemic hearts and two samples from nonischemic cardiomyopathic hearts. IL-1ß mRNA was detected with the use of biotinylated antisense oligonucleotides previously validated by Northern blot analysis. mRNA for IL-1ß was detected in luminal and capillary endothelium and intimal and adventitial macrophages (Figure, panel G), correlating with findings for IL-1ß protein. Occasional VSMCs also contained IL-1ß mRNA. Control sections (see "Methods") showed no hybridization for IL-1ß mRNA (Figure, panel H).
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Discussion |
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This study investigated the localization and production of IL-1ß in coronary arteries of humans with ischemic heart disease and nonischemic cardiomyopathy. This was achieved by performing immunolocalization for IL-1ß protein on histological sections of coronary artery specimens. Its cellular location was subsequently determined with the use of double immunostaining for IL-1ß together with markers for endothelial cells and macrophages. Furthermore, the expression of IL-1ß mRNA was localized by in situ hybridization histochemistry.
The main findings of this study were that luminal and adventitial vessel endothelial cells in human coronary arteries contain IL-1ß protein and its mRNA, and this observation was more marked in atherosclerotic coronary arteries. The amount of IL-1ß protein detected in the adventitial vessels correlated with the extent of atherosclerosis in coronary arteries from patients with ischemic heart disease. Less IL-1ß protein was detected in luminal endothelium compared with adventitial vessel endothelium. IL-1ß protein and mRNA were also present in a subset of coronary artery wall macrophages in patients with ischemic heart disease and nonischemic cardiomyopathy. The production of the IL-1ß protein corresponded to the presence of mRNA of this product throughout the vessel wall.
IL-1ß and IL-1 mRNA have previously been described in foam cells, smooth muscle cells, and endothelium in diet-induced iliac artery atherosclerotic plaques in monkeys,24 but there are no reports in the literature of IL-1ß mRNA and protein distribution in coronary arteries of humans with ischemic heart disease or nonischemic cardiomyopathy.
In one study IL-1 protein was detected in cultured macrophages isolated by shearing from human carotid artery plaque but not in intact macrophages within the vessel wall.23 Other studies in which RT-PCR was used have shown that IL-1 and IL-1ß mRNAs are increased in human atherosclerotic artery.22 Although RT-PCR serves as a highly sensitive technique, it does not always provide reliable quantitative data or accurate information about the cellular and regional localization of mRNA. To overcome these difficulties, we examined the cellular distribution of IL-1ß mRNA using in situ hybridization histochemistry.
The present study has demonstrated that IL-1ß is localized in vascular endothelium as well as in macrophages, with little IL-1ß detected in VSMCs. These findings were consistent in all patients with ischemic heart disease. Furthermore, the amount of IL-1ß protein in endothelial cells increased with the severity of atherosclerosis and with the apparent density of adventitial capillaries. The ages of the patients with nonischemic cardiomyopathy were 25, 45, 57, 59, and 60 years, with a mean age of 49.2 years. Four of these patients showed mild intimal hyperplasia and minimal IL-1ß in the luminal endothelium. Two of the older nonischemic cardiomyopathic patients with considerable intimal hyperplasia had IL-1ß in the adventitial vessels. These findings suggest that IL-1ß detected in coronary arteries from nonischemic cardiomyopathic hearts might be due to mild atherosclerosis in these arteries. There was no IL-1ß protein present in internal mammary or long saphenous vein sections. This indicates an important role for IL-1ß in the pathogenesis of atherosclerosis. The role of coronary artery IL-1ß in nonischemic cardiomyopathy is more difficult to define because all but one of the patients studied had mild coronary artery disease. This patient with normal coronary arteries did not show IL-1ß.
IL-1ß is involved in various different aspects of coronary artery pathophysiology. IL-1ß and IL-1 may play an important role in the development of complex plaques from fatty streaks,28 particularly by the stimulation of VSMCs, which is paramount in the development of atheromatous plaque.4 IL-1ß is known to stimulate the proliferation of VSMCs in vitro8 by the induction of platelet-derived growth factor AA29 and/or basic fibroblast growth factor.30 We detected little IL-1ß protein and its mRNA in VSMCs in coronary arteries, although other authors have shown that when appropriately stimulated, VSMCs synthesize and secrete IL-1ß.31 32 However, the IL-1ß detected within endothelial cells and macrophages in this study would be capable of acting on neighboring VSMCs to cause subsequent proliferation of these cells. In addition to its effects on VSMC proliferation, IL-1ß may be involved in destabilization of plaques by the stimulation of matrix metalloproteinases since it has been shown that IL-1 receptor antagonist inhibits the production of these enzymes by VSMCs.33
Many inflammatory cytokines including IL-1ß itself can stimulate the vascular endothelium to produce IL-1ß in an autocrine loop.28 34 This local production of IL-1ß may alter many functions of the endothelium. This cytokine has been shown to suppress endothelial cell proliferation35 ; in addition, endothelial cells exposed to IL-1ß express adhesion molecules, leading to adherence of leukocytes to endothelial surfaces.11 12 13 The adherence of monocytes and lymphocytes to the endothelium has previously been shown to be important in the development of atherosclerosis.37 The endothelium is also modified by IL-1ß to favor coagulation and thrombosis while impairing the fibrinolytic process.20 21 38 Cultured endothelial cells and VSMCs have been shown to produce prostaglandins and platelet-activating factor when stimulated by IL-1ß.39 40 These vasoactive substances may also play a role in the pathogenesis of atherosclerosis by altering the hemodynamics of blood flow. Atherosclerosis is an inflammatory process, and locally produced IL-1ß may activate or augment the synthesis of growth factors and other cytokines, leading to local inflammatory cascades. Furthermore, IL-1ß is involved in the proliferation or differentiation of monocyte-derived cells41 42 and increases vascular permeability.18
An increase in capillary vessels has previously been described in atherosclerosis.43 This study has also demonstrated an apparent increase in the density of capillaries in the adventitia and increased IL-1ß in adventitial capillary endothelial cells, which is significantly greater with increased severity of atheroma. A correlation has been described between the degree of neovascularization and intimal hyperplasia.44 Angiogenesis may result in activated endothelial cells, which will release mitogens that may subsequently cause SMC proliferation. Furthermore, adventitial microvessels are capable of invading the intima,42 where they may subsequently effect plaque development. IL-1ß identified in adventitial capillaries may be involved in neovascularization since it forms an autocrine loop with other cytokines and growth factors,28 eg, basic fibroblast growth factor, which is known to induce angiogenesis.30 45 46 47
In conclusion, this study has shown that IL-1ß is present in luminal and adventitial vessel endothelial cells and macrophages in coronary arteries from patients with ischemic heart disease. It is likely that this cytokine may contribute to the pathogenesis of atherosclerosis.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This research was supported in part by the Wellcome Trust and the Nuffield Foundation (UK). We are grateful to Dr Colin Clelland, Nottingham City Hospital (UK), for his advice on the cold processing of specimens for immunohistochemistry; Dr A. Kennedy, Consultant Cardiac Histopathologist, Northern General Hospital (Sheffield, UK), for his valuable advice on histological sections and for reading the manuscript; and Prof D.C. Crossman, Professor of Cardiology, University of Sheffield (UK), for his useful comments and advice. We are also grateful to Drs Ranjit Lall and Nicola Jones, Sheffield Statistical Service Unit, University of Sheffield, for performing the statistical analysis. We wish to thank the transplant surgeons T. Locke, J. Goiti, G. Wilkinson, and G.H. Smith and the transplant coordinators Yvonne Davenport and Karen Pearson for their valuable cooperation.
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Footnotes |
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Reprint requests to Dr Cathy M. Holt, Section of Cardiac Surgery, Clinical Sciences Centre, Northern General Hospital, Sheffield S5 7AU, UK. E-mail c.holt@sheffield.ac.uk.
Received August 10, 1995;
revision received December 15, 1995;
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