(Circulation. 1997;96:3328-3337.)
© 1997 American Heart Association, Inc.
Articles |
Upregulation of Angiotensin-Converting Enzyme During the Healing Process After Injury at the Site of Percutaneous Transluminal Coronary Angioplasty in Humans
From the Department of Geriatric Medicine, Osaka University Medical School, Suita, Osaka, Japan (M.O., H.R., A.O., A.K., K.K., J.H., T.O.); Department of Pathology, Osaka City University Medical School, Osaka, Japan (M.U.); Department of Cardiovascular Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (T.N., A.E.B.); and Second Department of Internal Medicine, Ehime University School of Medicine, Ehime, Japan (K.H.).
Correspondence to Toshio Ogihara, MD, Department of Geriatric Medicine, Osaka University Medical School, 2–2 Yamadaoka, Suita, Osaka 565, Japan.
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Abstract |
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Background Balloon injury models in rat have shown enhanced expression of ACE in the developing neointima. However, neointimal lesions in human coronary arteries are complex due to atherosclerosis and different types of wall laceration. This study was designed to investigate whether ACE is present in the neointima of humans, including patients with restenosis after percutaneous transluminal coronary angioplasty (PTCA).
Methods and Results Thirty-seven sites with angioplasty injury, obtained at autopsy, were studied using immunocytochemical techniques. Sites with injury limited to a fibrous plaque and those with injury extending into the media (<2 months after PTCA) showed fibrocellular repair tissue composed mainly of smooth muscle cells that were distinctly positive for ACE. In cellular reactions at the site of injury limited to the atheromatous plaque (<2 months after PTCA), the expression of ACE appeared first in accumulated macrophages; once smooth muscle cells appeared in the repair tissue, they also expressed ACE. At a later stage (3 months after PTCA), the number of cells with ACE expression decreased markedly; from 7 months on, ACE was no longer expressed within the repair tissue. Basically, there were no differences with regard to ACE expression during the healing process after PTCA between segments with and those without angiographic evidence of restenosis.
Conclusions These results show that PTCA injury in humans results in upregulation of ACE at sites of active repair and, therefore, ACE could play an important role as one of the mediators of the healing process after PTCA.
Key Words: angioplasty • angiotensin • atherosclerosis • coronary disease • immunohistochemistry
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Introduction |
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Restenosis, occurring in > 30% of patients within 3 to 6 months of PTCA,1-3 is the Achilles' heel of recent interventional cardiology. Although the mechanisms underlying restenosis remain unsolved, it is well known that neointimal proliferation, with SMCs as the prime cellular component, plays an essential role.4-7 Experimental studies have demonstrated that wound healing at the early stage after injury is promoted in the active repair sites as demonstrated by the phenotypic differentiation of SMCs8,9 and the expression of cytokines and growth factors such as PDGF ligands.10-12 Recently, evidence has accumulated that angiotensin II is one of the biological determinants involved in this process. In in vitro studies, angiotensin II has been shown to induce vascular SMC migration13 and growth.14,15 Rakugi et al16 demonstrated that the developing neointima expresses high levels of ACE 2 weeks after balloon injury in the rat aorta. Moreover, ACE inhibitors17,18 and angiotensin receptor antagonists19,20 prevent neointimal formation in balloon-injured rat artery. Of interest, the inhibition of vascular ACE activity in the injured site is strongly associated with the suppression of neointimal formation.18 These results suggest that ACE expression in the active repair sites after vascular injury plays an important role in wound healing processes.
The clinical relevance of these experimental findings to restenosis after PTCA in humans has been addressed in multicenter placebo-controlled trials (MERCATOR21 and MARCATOR22 studies). These trials demonstrated that an ACE inhibitor was not effective in preventing restenosis after PTCA. The discrepancy between the results in rats and humans may be due, at least in part, to the different nature of human atherosclerotic lesions and the wide variability of lesions in humans after PTCA. Another possibility is that ACE inhibitors at clinical doses may be insufficient to suppress vascular ACE in the repair tissue.
To our knowledge, however, ACE expression during wound healing processes after PTCA injury in humans has not been reported. We therefore investigated, with the use of immunocytochemical techniques, the expression of ACE at sites of postangioplasty lesions in human coronary arteries and whether ACE is expressed in active repair sites at the early stage after injury.
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Methods |
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Materials
The study material consisted of 37 dilated coronary arteries obtained at autopsy from 28 patients who had undergone an initial successful PTCA but subsequently died. The relevant clinical data are summarized in the Table
. No
patient had been treated with an ACE inhibitor within 5
days before death because of intubation or other clinical reasons.
Arterial segments in which a target lesion had been dilated
twice (5 segments) were included in the study, but those dilated three
or more times were excluded. Follow-up CAG had been performed in 20
dilated arteries (15 patients), and angiographic evidence of
restenosis was found in 13 arteries (9 patients). Angiographic
restenosis was defined as a loss of 
50% of the initial gain.
In other cases, no follow-up CAG had been done due to absence of
clinical symptoms of restenosis, noncardiogenic death within 2
months after PTCA, or death too early for evaluation of
restenosis (within 1 month after PTCA). As a consequence, 76%
of dilated lesions obtained >1 month after PTCA were evaluated for
restenosis with follow-up CAG. Of 9 patients with
restenosis, 8 patients had been subsequently treated: 6 with
repeated PTCA and 2 with coronary artery bypass graft surgery.
The remaining patient with restenosis had undergone no
interventional therapy because of renal failure.
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All autopsies were performed within 3 hours after death. The
localization of the angioplasty site was determined through precise
measurements of the distance in the angiograms at PTCA with the use of
coronary ostia and bifurcation sites as landmarks. The
coronary arteries were removed from the epicardial surface. The
segments containing the angioplasty site were sliced serially at
1-mm intervals. In 24 dilated arterial segments, slices
were snap-frozen, and in 13 dilated segments, slices were fixed in
methanol-Carnoy's fixative (60% methanol, 30% chloroform, and 10%
glacial acetic acid). From the same arterial segment, a
smaller distal segment, remote from the area that had contained the
balloon, was selected as a control and snap-frozen. The snap-frozen
samples were serially sectioned at 6-mm thickness and fixed in acetone.
Every first section was stained with hematoxylin and eosin. The other
sections were used for immunocytochemical staining. The
coronary slices fixed in methanol-Carnoy's solution were
processed routinely, embedded in paraffin, and serially sectioned at
5-mm thickness. From each slice, 30 serial sections were obtained.
Every eighth and ninth section was stained with hematoxylin and eosin
stain and Weigert's elastic van Gieson's stain, respectively. The
other sections were used for immunocytochemical staining.
Because histopathologically, plaque composition and the type of injury at the site of PTCA are very important factors in the healing processes after angioplasty injury in humans, injury sites were classified into three groups according to histological characterization: (1) injury limited to the fibrous plaque, (2) injury limited to the lipid-rich atheromatous plaque, and (3) injury extending into the media.5-7,23-27 Sites of injury limited to the atheromatous plaque show repair tissues with accumulation of macrophages, some SMCs, and the original cellular components of the plaque.24,26,27 In contrast, sites with injury extending into the media show extensive fibrocellular proliferation composed predominantly of SMCs.4-7 The actual site of angioplasty could always be traced because of a distinct laceration.
Immunocytochemistry
Antibodies
For the identification of ACE, we used a polyclonal antibody
generated against a 25-amino-acid peptide located near the COOH
terminus of human ACE. Five micrograms of rabbit serum antibody
inhibited >50% of catalytic activity of 0.1 U human kidney
enzyme.28 Its specificity has been
reported28,29 and was further confirmed through
the following methods. (1) We performed immunohistochemical
analysis using another kind of anti-ACE antibody, monoclonal
clone of 9B9 (Chemicon International), generated against human lung
ACE. The specificity of 9B9 has been previously
reported.30 (2) ACE activity was measured in the
kidney and native coronary artery as described below and
compared with immunohistochemical staining using polyclonal ACE
antibody. (3) ACE mRNA was also measured in the kidney and native
coronary artery using RT followed by PCR as described below and
compared with immunohistochemical staining. The coronary
segments used for the assays of ACE activity and mRNA expression were
selected to be adjacent to those used for immunohisto-chemical
investigations.
The primary monoclonal antibodies used for the identification of SMCs were anti-SMC actin markers: 1A4 (Dako Laboratories), HHF35 (Dako), and CGA7 (Enzo Laboratory). For endothelial cell identification, anti–von Willebrand factor (Dako) was used. EBM11 (Dako) and HAM56 (Dako) were used for the identification of macrophages. HLA-DR antibody (Becton and Dickinson) was used to examine the activation state of cells.31-34
Single Staining
Sections were incubated with the primary antibodies, either
overnight at 4°C or for 1 hour at room temperature. The labeled
streptavidin-biotin complex system with diaminoben-zidine, nickel
chloride color development (black) or with 3-amino-9-ethylcarbazole
development (red) was used. For the former, sections were
counterstained with methyl green; for the latter, sections were
counterstained with hematoxylin. Immunohistochemical staining of HLA-DR
was performed only with frozen sections because of its sensitivity.
Both positive and negative control experiments for ACE antibody were included in every set of experiments. The control study using human kidney tissue confirmed intense staining in proximal tubules and an absence of staining in the glomeruli. The negative control study using nonimmune rabbit serum (Dako) instead of the primary antibody also showed an absence of ACE immunoreactivity in the sections.
Immunodouble Staining
To identify cell types that express ACE, we performed
immunodouble staining with some of the sections. Immunodouble staining
was based either on two primary antibodies of different IgG subclasses
(1A4/EBM11) or on two primary antibodies of different animal species
(1A4/ACE and EBM11/ACE).35 In double staining for
1A4 and EBM11, we visualized the enzymatic activity of
ß-galactosidase for 1A4 in turquoise (BioGenex Kit) and the activity
of alkaline phosphatase for EBM11 in red (New Fuchsin Kit, Dako). In
double staining for 1A4/ACE and EBM11/ACE, alkaline phosphatase was
visualized with fast blue BB (blue: 1A4 and EBM11) and the peroxidase
with 3-amino-9-ethylcarbazole development (red: ACE).
Evaluation of Phenotypic Differentiation of SMCs
In this study, the differentiation state of SMCs within the
neointima at the site of PTCA was evaluated using two
anti-actin markers, HHF35 and CGA7, according to our previous studies
of immunophenotypic expression of neointimal SMCs in
coronary arteries after PTCA.4,36 Highly
differentiated SMCs stain positive with both HHF35 and CGA7, whereas
dedifferentiated SMCs stain negative with both HHF35 and CGA7, and
intermediately differentiated SMCs stain positive with HHF35 but
negative with CGA7.
Biochemical Analysis
ACE Activity Assay
Tissue ACE activity was determined using a fluorometric assay
modified from that described by Cheung and
Cushman.37 This assay measures the generation of
His-Leu from hippuryl-His-Leu (Sigma Chemical). Homogenized
tissue was incubated for 30 minutes at 37°C, pH 7.5, in the presence
or absence of hippuryl-His-Leu. The sensitivity of this assay is 
0.1
nmol/tube, and the generation of His-Leu is linear from 0.1 to
13 nmol/tube. ACE activity was calculated as nanomoles of
His-Leu generated per minute per milligram of protein. Protein was
measured with the BioRad protein assay system.
ACE mRNA Measurement
Total cellular RNA was obtained with RNazol B (Tel-Test)
according to the manufacturer's instructions. RT-PCR was performed
using GeneAmp EZ rTth RNA PCR kit (Perkin-Elmer Cetus).
Primers for ACE were 5'-TTGGAGGACCTG GTGGTGGCCAC-3' (forward) and
5'-AAAGTTGATGT CATGCTCGTCGCT-3' (reverse).38
These primers amplify a 216-bp fragment of human ACE,
nucleotides 2960 to 3175 of cDNA, which begins in exon 21
and terminates in exon 22 of the ACE gene. Primers for human
GAPDH were 5'-CCCATCACCATCTTCCAGGAG-3' (forward) and
5'-GTTGTCATGGATGACCTTGGC-3' (reverse).39 These
primers amplify a 284-bp fragment of human GAPDH,
nucleotides 211 to 495 of cDNA. The amplification profiles
consisted of RT at 65°C for 40 minutes and PCR with 35 cycles of
denaturation at 94°C for 1 minute, primer annealing at 60°C for 1
minute, and extension at 72°C for 1 minute. The first cycle
denaturation was for 4 minutes, and the last cycle extension was for 8
minutes. After the completion of RT-PCR, each amplified DNA was
electrophoresed through a 2% agarose gel.
Morphometric Analysis
The surface area occupied by ACE-positive cells within the
neointima was quantified with the use of a computerized
morphometry system, MacSCOPE Ver. 2.2 (Mitani Corporation), and
expressed as a percentage of the surface area occupied by 1A4-positive
SMCs within the neointima. In this morphometric
analysis, we studied neointimal lesions composed
mainly of SMCs, which were observed in a group with injury limited to
the fibrous plaque and a group with injury extending into the media. In
the group with injury extending into the media, a site obtained 5 days
after PTCA with no fibrocellular tissue response and sites dilated
twice by repeated PTCA (n=5) were excluded from the analysis.
The observer was blind to data regarding the patients' characteristics
and histological classification. Intraobserver
variability was determined on the basis of triplicate measurements. The
mean±SD differences among measurements was 3.6±0.4%. Statistical
analysis was performed using one-way ANOVA followed by
Fisher's PLSD test (StatView 4.02; Abacus Concepts).
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Results |
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Specificity of polyclonal ACE antibody was confirmed by comparison with immunohistochemical evaluation using monoclonal ACE antibodies and assays of ACE activity and mRNA expression (Figs 1
and 2).
Both polyclonal and monoclonal antibodies showed similar expression of
ACE in the proximal tubules of normal kidney and macrophages in
the intima of atherosclerotic lesions. Adjacent lesions of these
sections showed ACE activity and mRNA expression. ACE activity in
kidney and atherosclerotic lesion was 3.8 and 0.063 nmol/min/mg
of protein, respectively.
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X
DNA/Hae III digest.The 37 injury sites were divided into three groups as mentioned above: injury limited to the fibrous plaque (n=6, from 1 month to 5 months after PTCA); injury limited to the lipid-rich atheromatous plaque (n=15, from 5 days to 19 months after PTCA); and injury extending into the media (n=16; from 5 days to 17 months after single PTCA). All 5 segments dilated twice by repeated PTCA showed injury extending into the media.
Sites of injury limited to the fibrous plaque (within 2 months after
PTCA, n=5) showed reactive tissue composed mainly of SMCs. At this
stage, the neointimal SMCs expressed ACE (Fig 3). However, a segment obtained 5 months
after PTCA did not show any ACE expression in the repair tissue
(n=1).
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In contrast, sites of injury limited to the
atheromatous plaque (within 2 months after PTCA, n=14)
showed an initial accumulation of macrophages (Fig 4, left). These macrophages showed
co-localization with positive staining with anti-ACE antibody (Fig 4, center). The areas that stained positive for ACE coincided with those
that stained positive for HLA-DR (Fig 4, right). Once SMCs appeared in
the reactive tissue, they also expressed ACE. In a segment obtained 19
months after PTCA, ACE was no longer expressed in macrophages
or SMCs within the reactive tissue.
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Sites with post-PTCA injury extending into the media of
coronary arteries consisted of arteries dilated either once
(n=11) or twice (n=5). A site of injury obtained 5 days after PTCA
revealed no fibrocellular tissue response. Segments, 9 days to 2 months
after single PTCA (n=4), showed a fibrocellular repair tissue response
at the site of injury. Double staining with antibodies against SMCs and
against macrophages showed that the fibrocellular tissue was
composed mainly of SMCs with only a few macrophages (Fig 5, top left). ACE immunoreactivity was
detected in the neointimal SMCs and some of the
macrophages (Fig 5, top right and bottom left). These lesions
were positively stained with HLA-DR antibody (Fig 5, bottom right). The
neointima with medial injury, 3 to 6 months after PTCA
(n=4), consisted predominantly of SMCs with only occasional
macrophages, and a regenerated endothelial
layer was present at the luminal surface of the intima (Fig 6, left and middle). At this stage, ACE
expression was decreased in neointimal SMCs, but was
detected in regenerated endothelial cells (Fig 6, right). HLA-DR positive cells were also decreased in these lesions. The
fibrocellular tissue at sites with medial injury, from 7 months onward
(n=2), consisted almost entirely of SMCs, and the luminal surface was
covered with endothelial cells. ACE was no longer
expressed within the repair tissue except in the regenerated
endothelial cells. Arteries dilated twice by repeated
PTCA demonstrated a double layered fibrocellular response at the site
of injury. Both layers were composed predominantly of SMCs. Of 5
arteries dilated twice, 2 segments obtained within 5 months after the
second PTCA showed weak ACE expression in SMCs of the younger layer of
fibrocellular tissue. At these sites, the older layer of
neointima did not express ACE. The remaining 3 segments did
not reveal ACE expression within the repair tissue.
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Distal nontarget sites selected as control contained diffuse intimal thickening or mildly thickened fibrous intima, without appreciable lipid deposition and with some scattered macrophages. ACE staining was observed in the endothelial cells lining the luminal surface. Some macrophages within the fibrous intima also stained positive for ACE.
The relationship between phenotypic differentiation of SMCs and ACE expression was examined using anti-actin monoclonal antibodies, HHF35 and CGA7. Most of the highly differentiated SMCs in the neointima which stained positive with both HHF35 and CGA7 showed little ACE immunoreactivity. In contrast, most dedifferentiated and intermediately differentiated SMCs showed distinct positive staining for ACE.
Morphometric Analysis
The results of the morphometric analysis are shown in Fig 7. The ACE-positive cell area, expressed
as a percentage of the 1A4-positive SMC area, was significantly higher
in the sites within 2 months after PTCA than in the sites from 3 months
on.
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Restenosis Versus Nonrestenosis Lesions
In the present study, angiographic restenosis was
found in 13 arteries (Table
). Basically, segments with and without
angiographic evidence of restenosis showed no appreciable
difference in ACE expression.
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Discussion |
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This is the first study to demonstrate the expression of ACE in human coronary arteries after PTCA. We investigated ACE expression not only in endothelial cells but also in macrophages and intimal SMCs. Furthermore, we demonstrated that the major cell types expressing ACE were quite different depending on whether the injury at the site of PTCA extended into the media or was limited to the plaque. Sites of injury limited to the atheromatous plaque showed strong ACE expression in macrophages at the early stage of the healing process. In contrast, sites with injury extending into the media showed extensive fibrocellular proliferation composed predominantly of SMCs associated with ACE expression. To our knowledge, Aschoff et al38 are the only researchers to demonstrate that human medial SMCs express ACE. They detected ACE mRNA in cultured SMCs of the human pulmonary artery through the use of RT-PCR. Although we cannot exclude a possibility of ACE expression in medial SMCs of the human coronary artery due to methodological limitation of immunohistochemical technique, ACE expression in the neointimal SMCs after PTCA was obviously significant.
Furthermore, our findings indicate that ACE may be upregulated only at the early stages, within 2 months after PTCA, at the lesions with macrophages migrating to the injury site and SMCs proliferating and/or migrating in the repair tissue. It is likely that the initial increase in ACE in the repair tissue is associated with an influx of inflammatory cells because it is reported that ACE is expressed in human monocytes38-40 and that ACE activity increases up to 100-fold during in vitro differentiation from monocytes to macrophages.41
We further investigated whether repair sites with ACE-expressing cells are in the active state. It has been reported that tissue repair after PTCA injury is actively promoted, accompanied with phenotypic dedifferentiation of SMCs in humans.4,36 HLA-DR is also an important marker as the activation state. It has been demonstrated that HLA-DR is absent from cells of normal arteries but appears in atherosclerotically transformed tissue, which are composed of macrophages, T cells, and SMCs.31,33 Tanizawa et al42 reported that HLA-DR was expressed in the healing processes at the early stage after PTCA. The expression of ACE in most dedifferentiated and intermediately differentiated SMCs and its well colocalization with HLA-DR strongly suggest that ACE-expressing cells in the neointima are in the active state.
We previously demonstrated, using immunohistochemical investigations
and in situ hybridization, that the repair tissue at the early stage
after PTCA in humans expressed PDGF-B chain, a
representative of growth factors, in
macrophages and 
-actin–negative spindle cells accompanied
with good coexpression of HLA-DR; the latter most likely were
dedifferentiated SMCs.42,43 This evidence
recognizes that ACE expression is consistent with PDGF-B chain
expression in cell components and the duration after PTCA. These
results also suggest that ACE is upregulated at the sites of active
repair.
It is likely that there is an interaction involving ACE expression between SMCs and macrophages because some SMCs expressing ACE are colocalized with macrophages. Battle et al44 showed that ACE activity in primary cultured rat SMCs could be induced by dexamethasone. Fishel et al45 reported that fibroblast growth factor stimulated ACE expression in rat vascular SMCs. Fibroblast growth factor is known to be released from macrophages.11 Taken together, these results imply that the expression of ACE in SMCs may be regulated, in addition to the phenotypical regulation of SMCs, by unknown factors derived from macrophages such as fibroblast growth factor.
What is the clinical relevance of ACE upregulation in coronary arteries after PTCA? A major role of ACE is believed to be hydrolysis of angiotensin I and bradykinin. A number of studies using cultured cells and animal models have revealed that angiotensin II plays an important role in vascular remodeling.46 It has been reported that angiotensin II stimulates the growth and migration of human SMCs15,47 and enhances the synthesis of extracellular matrix48 via the type 1 angiotensin II receptor and that the overexpression of type 2 angiotensin II receptors in arteries prevents neointimal formation after balloon injury in rats.49 Furthermore, the vasoconstrictive action of angiotensin II may contribute to constrictive remodeling after PTCA. These findings suggest that ACE is involved in the healing process after PTCA injury in human coronary arteries via local production of angiotensin II. It should be clinically important to investigate the effects of ACE inhibitors on ACE expression. In the present study, we could not investigate those effects in the repair lesions because of the limitation of our study that none of the subjects had been treated with ACE inhibitors within 5 days before death. Previous clinical trials21,22 demonstrated that the ACE inhibitor cilazapril had no effect on restenosis after PTCA in humans. Our finding that upregulation of ACE after PTCA was observed in segments with and without angiographic evidence of restenosis appears to be consistent with the outcome of these clinical trials. However, the number of segments defined as angiographic restenosis in our study might be too small to conclude the role of ACE expression in restenosis after PTCA. Further studies to investigate the effects of ACE inhibitors on ACE expression and the relation between ACE expression and restenosis, using not only immunohistochemical methods but also ACE activity and mRNA assays, may provide further information about the role of ACE expression at the early stage in the wound healing process.
In summary, the present study provides data that ACE is upregulated as part of the repair processes after PTCA injury in humans. Numerous studies have revealed that various cytokines such as PDGF, basic fibroblast growth factor, and transforming growth factor-ß and vasoactive substances, including angiotensin II, are involved in the healing process after angioplasty in animal models. Some of these factors have been shown to contribute to the healing process in human PTCA lesions.42,43,50,51 The present study demonstrated that ACE, an important factor for generating angiotensin II, is another mediator in the healing process of human coronary arteries after PTCA.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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We are indebted to Akiko Kojima and Yuka Ohishi for their excellent technical assistance.
Received March 26, 1997; revision received July 14, 1997; accepted August 1, 1997.
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