© 1996 American Heart Association, Inc.
Articles |
ßig-h3, a Transforming Growth Factor–ß–Inducible Gene, Is Overexpressed in Atherosclerotic and Restenotic Human Vascular Lesions
From the Departments of Pathology and Medicine (E.R.O'B., M.R.G., T.W.Z., S.M.S.), University of Washington School of Medicine, Seattle; Bristol Myers Squibb (K.L.B., A.P.), Seattle, Washington; Sequoia Hospital (T.H., J.B.S.), Redwood City, Calif; Kokura Memorial Hospital (T.K., M.N.), Kitakyushu, Japan; and the Department of Medicine (H.M.), University of British Columbia, Vancouver, Canada.
Correspondence to Edward R. O'Brien, MD, FRCP(C), Department of Medicine (Cardiology), Vascular Biology Laboratory, University of Ottawa Heart Institute, 1053 Carling Ave, Ottawa, Ontario, Canada K1Y 4E9. E-mail eobrien@ohi-net.heartinst.on.ca.
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Abstract |
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Abstract Transforming growth factor–ß (TGF-ß) plays an important role in vascular lesion formation and possibly the renarrowing process ("restenosis") that occurs after balloon angioplasty. Secreted in a latent form by most cells, TGF-ß requires enzymatic conversion before it is biologically active. TGF-ß–inducible gene h3 (ßig-h3) is a novel molecule that is induced when cells are treated with TGF-ß1. This study examined the expression of ßig-h3 in normal and diseased human vascular tissue. To determine the expression pattern of ßig-h3 in human arteries, immunocytochemistry was performed on tissue sections from (1) normal internal mammary arteries, (2) the proximal left anterior descending coronary artery (with minimal intimal thickening) of 15 patients aged 18 to 40 years, (3) primary and restenotic coronary lesions from 7 patients, and (4) fresh directional atherectomy tissue from 11 patients. A polyclonal antibody consistently immunodetected ßig-h3 protein in endothelial cells of all vascular tissue. In normal coronary arteries of young individuals, ßig-h3 protein was absent from the intima and media but was found in the subendothelial smooth muscle cells of some arteries with modest intimal thickening. In diseased arteries ßig-h3 protein was more abundant in the intima than the media. Restenotic coronary lesions tended to show higher levels of immunodetectable ßig-h3 protein, especially in areas of dense fibrous connective tissue. ßig-h3 protein was immunodetected in the cytoplasm of plaque macrophages as well as smooth muscle and endothelial cells. By using in situ hybridization on fresh directional atherectomy specimens, we found ßig-h3 mRNA to be overexpressed by plaque macrophages and smooth muscle cells. Nondiseased human internal mammary arteries also expressed ßig-h3 mRNA in endothelial cells but not in the smooth muscle cells of the normal intima and media. These results document the expression of ßig-h3 in diseased human arterial tissue and support the hypothesis that active TGF-ß plays a role in atherogenesis and restenosis.
Key Words: transforming growth factor–ß–inducible gene h3 • transforming growth factor–ß • atherosclerosis • restenosis
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Introduction |
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A central event in tissue repair is the release of cytokines in response to injury. Several lines of evidence point to TGF-ß as a key cytokine that initiates and terminates tissue repair. Sustained production of TGF-ß may be associated with the development of tissue fibrosis and wound contracture.1 The role of TGF-ß in the vessel wall is complex, as this molecule can function as a growth promoter or inhibitor as well as regulate the synthesis of ECM molecules, proteases, and protease inhibitors.1 2 3 TGF-ß is synthesized and stored at the cell surface and in the ECM as a latent propeptide with no known biological activity; it requires proteolytic cleavage before it is biologically active.4 One approach to studying the function of active TGF-ß is to examine biological events that are the result of its action. Several investigators have treated cells with TGF-ß and used differential screening of cDNA libraries to identify novel genes that are induced by TGF-ß in an effort to identify potential biological markers of TGF-ß activity.5 6 7 ßig-h3 is a molecule that was first cloned from a cDNA library constructed from human lung adenocarcinoma cells that were growth arrested with TGF-ß1 for 72 hours.8 ßig-h3 has been identified through differential hybridization screening as a cDNA that was uniquely induced by TGF-ß. ßig-h3 is a 683–amino acid–secreted protein that contains an Arg-Gly-Asp (RGD) sequence and four internal repeat domains that are homologous with fasciclin I, an intercellular adhesion molecule.9 10 While studies on the biological function of ßig-h3 have only recently begun, preliminary data suggest that this molecule is a matrix molecule that may be involved in cell adhesion and carcinogenesis.11 12 13 14 15
The purpose of this study was to determine whether ßig-h3 is expressed in human vascular tissue, and if so, at what stage in the development of primary and restenotic coronary lesions. The results indicate that overexpression of ßig-h3 parallels the development of atherosclerosis and may play an important role in arterial scarring after angioplasty.
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Methods |
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Sources of Human Vascular Tissue
Human coronary artery specimens with various stages of atherosclerosis were collected from the sources listed below after obtaining the approval of the respective institutional review committees.
Postmortem Coronary Arteries: Early and Advanced
Lesions
Postmortem coronary arteries from 14 men and 1 woman
(aged 18 to 40 years) who died as a result of trauma were collected
from the coroner's service at the Vancouver Hospital and Health
Sciences Center in Vancouver, Canada. All coronary arteries
were retrieved within 2 to 6 hours of death and immersion-fixed in
10% neutral buffered formalin. Only the proximal left anterior
descending coronary artery, a site prone to
atherosclerosis, was studied.16 In
addition, postmortem coronary artery cross sections were
obtained from patients with coronary artery disease who
underwent antemortem coronary angioplasty at Kokura Memorial
Hospital, Kitakyushu, Japan.17
Coronary tissue samples from both primary and
restenotic lesions of 7 men (mean age, 73 years; range, 55
to 87 years) who died as a result of cardiogenic shock related to
coronary restenosis (4), acute myocardial
infarction due to the presence of a new lesion (1), renal failure (1),
and liver cirrhosis (1) were also studied. Postmortem, the
restenotic coronary artery segments were identified
according to the location of arterial side branches that
were identified angiographically at the time of the original
angioplasty. The median interval between the last angioplasty and death
was 110 days (range, 39 to 552 days). All coronary arteries
from Japan were perfusion-fixed with 1.4%
glutaraldehyde and immersion-fixed in 20% neutral
buffered formalin. By using a computerized image-analysis
system (Bioscan Optimus) the extent of arterial narrowing
was assessed on Verhoeff–van Gieson–stained slides. Lumen
area (LA) and plaque area (PA) (ie, the area encompassed by the
internal elastic lamina) were manually traced. The percentage area
stenosis was defined as 1-(LA/PA)x100. Cross sections
with the most severe stenoses were selected for
immunocytochemical studies.
Freshly Fixed Vascular Tissue for the Detection of mRNA
Expression
To assess ßig-h3 mRNA expression in normal vascular
tissue, fresh tissue from the internal mammary arteries of two patients
undergoing coronary artery bypass grafting surgery was
collected in 10% neutral buffered formalin. Directional atherectomy
specimens from 2 women and 9 men with ischemic syndromes
(median age, 72 years; range, 50 to 80 years) were used to assess
ßig-h3 expression in diseased vascular tissue. The latter tissue
specimens were derived from 1 primary and 1 restenotic
coronary artery lesion, 3 saphenous venous bypass graft lesions
(2 primary and 1 restenotic), and 6 restenotic
peripheral arterial lesions.
Control Tissue
CHO cells transfected with the expression vector pEE-14
containing the ßig-h3 cloning region were used as positive
control tissue for the expression of ßig-h3 mRNA and
protein.8 In addition, CHO cells transfected with a pEE-14
plasmid that did not contain the ßig-h3 cDNA were used for
negative control studies. Cells were grown in tissue culture,
trypsinized, and centrifuged into a pellet before being
immersion-fixed in 10% neutral buffered formalin.
Immunocytochemistry
All tissue sections were paraffin-embedded, and
immunocytochemistry was performed on 5-µm sections.18
Briefly, slides were deparaffinized, and endogenous
peroxidase activity was blocked with H2O2
before the specific primary antibody or preimmune serum was applied for
60 minutes at room temperature. A biotinylated anti-rabbit
secondary antibody was then applied for 30 minutes followed by an
avidin-biotin-peroxidase conjugate (ABC Elite, Vector
Laboratories) for 30 minutes at room temperature. A standard peroxidase
enzyme substrate (3,3'-diaminobenzidine) with or without nickel
chloride was added to yield black or brown reaction products,
respectively. For each anti–ßig-h3 immunocytochemistry run, CHO
cells transfected with ßig-h3 were used as a positive control;
they consistently displayed intense black (or brown)
immunolabeling, a reaction product that we have defined as our
standard of positive immunolabeling for ßig-h3. Tissue slides for
all postmortem and directional atherectomy tissue samples were
immunolabeled with a rabbit anti-human ßig-h3 antiserum
(titer, 1:1000). This antiserum was made to the portion of the
ßig-h3 sequence that codes for amino acids 210 through
683.13 For negative control studies, rabbit preimmune
serum was substituted for the polyclonal anti–ßig-h3 primary
antibody. CHO cells transfected with a pEE-14 plasmid that did not
contain the ßig-h3 cDNA were also used for negative control
studies. To estimate the amount of ßig-h3 protein found in
postmortem coronary artery cross sections, two blinded
investigators graded the extent of ßig-h3 protein immunodetected
on each slide. The following grading system was used to semiquantify
the amount of ßig-h3 protein on each slide: 0, absent; 1+, 
5%
of the tissue; 2+, 5% to 20% of the tissue; 3+, 21% to 50% of the
tissue; and 4+, >50% of the tissue. The following antibodies were
applied to adjacent slides to determine the identity of cells
expressing ßig-h3 mRNA or protein: anti–smooth
muscle–
-actin to identify SMCs, anti–CD-68 to identify
macrophages, and anti–HPCA-1 (CD-34) antibody to identify
ECs.18
In Situ Hybridization
A 2691-bp human cDNA to ßig-h3 was isolated from A549
human lung adenocarcinoma cells that were treated with TGF-ß1 for 72
hours.8 By using a pBluescript SK+ plasmid transcription
vector containing the ßig-h3 cDNA, [35S]UTP-labeled
anti-sense and sense riboprobes were generated with T3 or T7
polymerase after linearizing the plasmid with HindIII and
Xba I, respectively. The riboprobes were hybridized to
tissue slides at 55°C overnight before being washed briefly in 2x
saline–sodium citrate followed by 0.1x saline–sodium citrate
for 2 hours at 55°C. After drying overnight, the slides were dipped
in Kodak NTB2 emulsion and stored in lightproof desiccated boxes at
4°C and developed after 3 weeks. Only fresh directional atherectomy
specimens and internal mammary arteries that had been promptly fixed in
10% neutral buffered formalin were used to demonstrate ßig-h3
mRNA expression in situ. Postmortem coronary arteries with or
without disease were not used for the in situ hybridization studies as
we were concerned that tissue autolysis with degradation of mRNA may
obscure the results.
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Results |
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Control Studies
To determine the specificity of the rabbit polyclonal antiserum to ßig-h3, cells transfected with ßig-h3 were immunolabeled with this antiserum. Rabbit polyclonal ßig-h3 antiserum routinely immunolabeled CHO cells transfected with the ßig-h3 cloning region, whereas rabbit preimmune serum did not immunolabel any of the study tissues. The ßig-h3 anti-sense riboprobe hybridized with CHO cells transfected with ßig-h3, whereas the corresponding sense riboprobe showed minimal background signal for all study slides. The polyclonal ßig-h3 antiserum and riboprobe, respectively, failed to immunolabel and hybridize with CHO cells transfected with a pEE-14 plasmid that did not contain the ßig-h3 cDNA.
Normal ECs Express ßig-h3 Protein and mRNA
ECs lining the central lumen of normal internal mammary
arteries were found to express ßig-h3 protein and mRNA (Fig 1A
and 1B). Similarly, the ECs of adventitial microvessels
also expressed ßig-h3 protein and mRNA. In contrast, the SMCs of
normal intima and media did not express ßig-h3 mRNA or
protein.
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Postmortem Coronary Arteries With Early and Advanced
Lesions
Thirteen of the 15 proximal left anterior descending
coronary artery cross sections from young trauma victims had
diffuse intimal thickening without evidence of
atherosclerosis. All specimens were morphologically
intact and consistently immunolabeled with an antibody to
-actin. Typically, the intima of these arteries was one to two
times the thickness of the media and consisted entirely of SMCs (Fig 1C
). All 15 specimens displayed faint to intense ßig-h3
immunolabeling in ECs lining the central lumen as well as the
endothelium of some adventitial microvessels. SMCs in
the media and intima were immunonegative for ßig-h3 protein,
apart from two specimens with positive immunolabeling of
stellate-shaped SMCs in the subendothelium (Fig 1D).
The histologies of the postmortem primary and restenotic
coronary lesions were similar in many ways (Fig 2). All lesions demonstrated lumenal narrowing
(percentage area stenosis of primary versus
restenotic lesions, 77±14% and 84±8%, respectively,
mean±SD; P=.24) (Table). Four of the primary
and 3 of the restenotic lesions had necrotic cores, and 2
primary and 3 restenotic lesions had discrete areas with
stellate-shaped SMCs. ßig-h3 protein was less abundant
(grades 0 to 2+) in coronary artery cross sections from primary
atherosclerotic lesions (Fig 2A and 2B). Conversely, cross sections of
restenotic coronary artery lesions had more
immunodetectable ßig-h3 protein (grades 1+ to 4+) (Fig 2C through
2E). A comparison of pairs of specimens from the same patient (ie,
primary versus restenotic lesions) showed a trend toward
more immunodetectable ßig-h3 protein in arteries that had been
treated with angioplasty (Table). ßig-h3 protein was
predominantly detected extracellularly in the dense, fibrous ECM
surrounding the atherosclerotic core and adjacent to focal collections
of macrophages and SMCs (Fig 2E through 2G). Moreover, the
media of some of the postangioplasty arteries immunolabeled for
ßig-h3. While stellate-shaped SMCs commonly displayed
perinuclear ßig-h3 immunolabeling, the levels of ßig-h3
protein in the ECM surrounding these cells appeared to be less than
those seen in adjacent hypocellular areas with dense connective tissue.
These dense connective tissue areas constituted the fibrous cap of
these complex lesions. In some specimens ECs lining the main
arterial lumen as well as intraplaque and adventitial
microvessels were immunopositive for ßig-h3.
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Expression of ßig-h3 mRNA by Plaque SMCs and
Macrophages
To determine whether ßig-h3 mRNA is expressed in
arterial wall tissue, freshly fixed directional atherectomy
tissue was used for in situ hybridization studies. These specimens
consisted of tissue with a wide array of histomorphologies (eg,
hypercellular, fibrotic, and inflammatory foci). In the small number of
primary and restenotic atherectomy specimens that were
examined, varying amounts of ßig-h3 protein were immunodetected
in all atherectomy specimens in patterns similar to those described for
the atherosclerotic and restenotic coronary artery
cross sections. In particular, dense connective tissue showed high
levels of ßig-h3 immunolabeling (Figs 3C and 4B). There were no differences in the distribution
pattern or extent of immunodetectable ßig-h3 protein present
in primary or restenotic atherectomy specimens. It should
be noted, however, that it is impossible to determine the nature of the
tissue collected when directional atherectomy is performed. In other
words, tissue that is resected from a restenotic lesion may
not necessarily include or exclusively represent new tissue
mass that may have arisen as part of a restenotic process.
Four of the 11 atherectomy specimens (1 primary saphenous venous bypass
graft lesion, 2 primary peripheral arterial
lesions, and 1 restenotic peripheral
arterial lesion) had focal cellular areas that specifically
hybridized with the ßig-h3 riboprobe. For example, ßig-h3
mRNA was found to be expressed by macrophages (Fig 3A through
3F). In addition, stellate-shaped SMCs displayed very intense
hybridization levels (Fig 4A through 4E). ECs of the surface
endothelium or intraplaque microvessels were not
present in these specimens. ßig-h3 mRNA expression was always
found in or adjacent to areas of the plaque with immunodetectable
ßig-h3 protein. We were unable to identify
histological features that are predictive of
ßig-h3 expression or lack of expression. Also, since we did not
have the complete clinical profile of patients whose tissue was
examined in this study, we were at a loss to correlate clinical
features with ßig-h3 expression patterns.
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Discussion |
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These studies demonstrate that ßig-h3, a TGF-ß–inducible molecule, is expressed in parallel with the progression of coronary atherosclerosis and may play an important role in the genesis of primary and restenotic vascular lesions. In human coronary arteries free of advanced disease, ßig-h3 is not expressed by the SMCs that constitute benign intimal thickening. However, as lesion mass accumulates, stellate-shaped SMCs in the subendothelium express ßig-h3 protein. In advanced atherosclerosis, ßig-h3 is expressed by plaque macrophages as well as stellate-shaped SMCs and is prominent extracellularly in the dense fibrous tissue adjacent to these cells. ECs lining the main arterial lumen and adventitial microvessels express ßig-h3 mRNA and protein regardless of the stage of vascular disease. Postmortem coronary artery cross sections with restenotic lesions appeared to have more immunodetectable ßig-h3 than primary lesions, but this comparison was limited by the small number of specimens that were examined and the difficulties that are inherent with the quantification of immunocytochemistry results. In directional coronary atherectomy specimens there was no obvious difference in the expression pattern of ßig-h3 mRNA or protein in tissue resected from primary compared with restenotic lesions.
The intracellular and extracellular distributions of ßig-h3 protein that were documented in this study are similar to those described for TGF-ß in experimental arterial lesion formation. For example, in the rat carotid artery balloon-injury model, neointimal TGF-ß mRNA expression increases within 6 hours of balloon injury and remains elevated for at least 2 weeks.2 3 In human coronary arteries TGF-ß protein is primarily expressed in the subendothelial layer of an intima that is rich in proteoglycans, while lesser amounts are found in musculofibrous layers.19 In coronary atherectomy specimens, TGF-ß mRNA is overexpressed by stellate-shaped SMCs resected from restenotic lesions.20 21 Finally, it is interesting to note that the vascular expression pattern of ßig-h3 parallels that of osteopontin, another TGF-ß–inducible molecule.18
The biological function of ßig-h3 is an area of ongoing research.11 12 13 15 Preliminary data suggest that this molecule may play a key role in cell adhesion, as recombinant ßig-h3 protein supports the attachment and spreading of dermal fibroblasts.15 Less is known about the biology of TGF-ß and ßig-h3 in vascular lesion formation and progression, but certain ideas can be put forward. For example, both TGF-ß and ßig-h3 are expressed as plaque mass accumulates and lumenal narrowing occurs.2 20 22 23 Stellate-shaped SMCs are common to both early atherosclerotic lesions as well as restenotic arterial segments and overexpress both molecules. In contrast, SMCs that constitute benign intimal thickening are essentially devoid of these molecules. Stellate-shaped SMCs have a distinct morphology that is often associated with an activated SMC phenotype, and hence these cells are presumed to represent replicative foci in plaques.17 24 25 However, it is questionable whether cells in these areas of the plaque have recently proliferated, as replication is an infrequent and modest event in atherosclerotic and restenotic human coronary artery tissue.26 27 28 Moreover, TGF-ß may be a key inhibitor of atherosclerosis, although this notion may be an oversimplification of the complex role of this pivotal cytokine in advanced atherosclerosis.29 30 31 Indeed, if TGF-ß were solely a negative regulator of growth, then one would expect that as atherosclerosis develops cells producing high levels of TGF-ß would die rather than survive and spread. Similarly, in TGF-ß knockout mice, EC proliferation does not occur; instead there is defective EC differentiation.32 Therefore, although abrogation of TGF-ß negative growth regulation may be necessary for the transformation of a quiescent, normal arterial wall segment into a complex vascular lesion, it is likely that TGF-ß may also be involved in the enhancement of cell proliferation, migration, and ECM synthesis in later stages of atherogenesis.2 3 22 33 34 Plaques that are rich in stellate cells may represent foci of vascular cell migration and ECM synthesis.35 Overexpression or unregulated expression of ßig-h3 (or TGF-ß) in these areas may cause excessive tissue repair and the genesis of abundant scar tissue, much like keloid formation.36 37 ßig-h3 may be particularly important in expanding these processes by reducing local cell adhesion, facilitating cell migration, and/or promoting the synthesis of ECM molecules. The administration of exogenous TGF-ß or transfection of TGF-ß clearly induces fibrosis in various tissues, including the artery wall.2 22 34 38 Similarly, various forms of TGF-ß antagonism or knockout result in a decrease in experimental scar formation.3 39 40 41 ßig-h3 is associated with matrix proteins in cartilage; in an enzyme-linked immunosorbent assay recombinant ßig-h3 bound with purified type II collagen and fibronectin but not collagen type IV (K.L.B., unpublished data, 1995). Taken together, these data suggest that ßig-h3 may be an important matrix molecule. Finally, wound contraction may be an important process in vascular wall healing and result in inappropriate arterial wall remodeling with lumenal narrowing. Preliminary data from a porcine model of coronary artery disease suggest that adventitial scarring is an important determinant of arterial lumen caliber and that adventitial expression of ßig-h3 increases after serial balloon injury.23 42 Studies aimed at attenuating wound healing after arterial injury may provide novel therapeutic strategies for the clinical management of coronary artery disease.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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These studies were supported by National Institutes of Health grants HL42270 and HL47151, the Pacific Foundation for Cardiovascular Research, and the Heart and Stroke Foundation of Ontario. This work was initiated while Dr O'Brien was a Research Fellow of the Medical Research Council of Canada. Currently, Dr O'Brien is a Research Scholar of the Heart and Stroke Foundation of Canada. The authors are indebted to Jackie Lee for coordinating atherectomy tissue collection at Sequoia Hospital as well as the many clinicians at the other participating centers who helped with the collection of human vascular tissue specimens.
Received August 1, 1995; accepted December 18, 1995.
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