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(Circulation. 2000;101:296.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Inhibition of Late Vein Graft Neointima Formation in Human and Porcine Models by Adenovirus-Mediated Overexpression of Tissue Inhibitor of Metalloproteinase-3
From the Bristol Heart Institute, University of Bristol, Bristol, UK. Dr Baker’s current address is Dept of Medicine and Therapeutics, University of Glasgow, Western Infirmary, Glasgow G116NT, UK.
Correspondence to Sarah J. George, PhD, Bristol Heart Institute, University of Bristol, Level 7, Bristol Royal Infirmary, Bristol BS2 8HW, UK. E-mail s.j.george{at}bris.ac.uk
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Abstract |
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Background—Autologous saphenous vein coronary artery bypass graft surgery is complicated by late graft failure due to neointima formation and subsequent atherosclerosis. Growth factors and metalloproteinases (MMPs) act in concert to promote neointima formation. Tissue inhibitor of metalloproteinase-3 (TIMP-3), an extracellular matrix–associated MMP inhibitor, uniquely promotes apoptosis of isolated vascular smooth muscle cells. Here, we overexpressed TIMP-3 at the luminal surface of human saphenous veins before organ culture and in pig saphenous veins before interposition grafting into carotid arteries in vivo to assess neointima formation.
Methods and Results—In both models, high TIMP-3 immunoreactivity occurred in the luminal and upper medial extracellular matrix after adenovirus delivery. MMP activity measured by in situ zymography was reduced throughout the veins, confirming a bystander effect. By use of 3 independent techniques, apoptosis levels in the neointima and medial layer were significantly elevated by TIMP-3 overexpression. Neointima formation was reduced by 84% in 14-day human organ cultures and by 58% in 28-day pig vein grafts (both P<0.05). In contrast, TIMP-2 overexpression had no effect on neointima formation in vivo.
Conclusions—Our results highlight the potential therapeutic benefit for TIMP-3 overexpression to reduce neointima formation associated with late vein graft failure.
Key Words: metalloproteinases • genes • viruses • grafting • neointima
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Introduction |
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Coronary artery bypass graft surgery is initially effective in relieving the symptoms of angina and prolongs survival. Arterial conduits are preferred, but the requirement for multiple grafts results in the use of autologous saphenous vein. Late vein graft failure occurs as a result of neointima formation and superimposed atherosclerosis, resulting in a 30% to 50% failure rate within 10 years.1 Because of the lack of effective pharmacological interventions for treatment of late vein graft failure, we have focused on the possibility of using a gene-based therapy.
Matrix-degrading matrix metalloproteinases (MMPs) have been implicated in the progression of vascular diseases.2 3 4 5 Together, MMPs can degrade all components of the extracellular matrix (ECM),6 and dysregulation of MMPs promotes migration and/or proliferation of vascular smooth muscle cells (SMCs). MMP activity is regulated by binding of endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), a family of 4 members,7 8 9 10 to both pro-MMPs and active forms of MMPs.11 12 13 14 15
Recently, the role of MMPs in vascular pathologies has been substantiated by TIMP overexpression studies. Overexpression of TIMP-1 or -2 inhibits neointima formation in the rat model of angioplasty restenosis and in an in vitro human model of vein graft neointima formation.16 17 18 19 20 Overexpression of TIMP-3, but not TIMP-1 or -2, promotes apoptosis of SMCs.21 This novel function prompted us to define whether TIMP-3 would be useful as a novel gene therapeutic approach for prevention of vein graft neointima formation.
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Methods |
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Materials
Unless stated, all chemicals were obtained from Sigma. Media, antibiotics, and FCS were purchased from Gibco/BRL; nucleotides from Boehringer Mannheim; and enzymes from Promega. Replication-defective recombinant adenoviruses RAdlacZ (reporter gene), RAdTIMP-2 (human TIMP-2), and RAdTIMP-3 (human TIMP-3) have been described elsewhere.21
Adenovirus-Mediated Infection of Human Saphenous Vein and
Subsequent Organ Culture
Luminal delivery of adenoviruses to human saphenous vein was
performed as described.18 Briefly, 4- to 6-cm segments
were cannulated, and the luminal surface was exposed to adenovirus at
1.2x1010 pfu/mL at
physiological pressure for 1 hour. Segments of vein
were cultured for 14 days in RPMI 1640 medium containing 30% FCS and
antibiotics.
Infection of Pig Saphenous Vein and Graft Procedure
The saphenous vein from each hind limb of 20- to 30-kg Landrace
pigs was surgically exposed, and the side branches were ligated. The
vein was placed in sterile medium, cannulated, and flushed and infused
with vehicle (10 mmol/L Tris-HCl, 125 mmol/L NaCl, 1
mmol/L MgCl2, pH 7.4) or adenovirus at
2.5x1010 pfu/mL without distension for 30
minutes at room temperature. Heparin (100 IU/kg) was administered
systemically, and the vein was anastomosed as an end-to-end
interposition graft into each common carotid artery.22 The
pigs were maintained on a normal chow diet for 7 or 28 days before
explantation.
Localization of Transgene Production and Other
Immunocytochemical Procedures
For analysis of ß-galactosidase expression, explanted
grafts were stained with X-gal stain [100 mmol/L sodium
phosphate, pH 7.3 (77 mmol/L
Na2HPO4, 23 mmol/L
NaH2PO4), 1.3 mmol/L
MgCl2, 3 mmol/L
K3Fe(CN)6, 3 mmol/L
K4Fe(CN)6, and 1
mg/mL X-gal
(5-bromo-4-chloro-3-indoyl-ß-D-galactopyranosidase)] for
16 hours at 37°C. Staining was photographed en face, and the veins
were then cross-sectioned and stained with nuclear fast red stain.
Immunocytochemistry was performed with a monoclonal anti–human TIMP-3
antibody (TCS Biologicals). Briefly, frozen sections were incubated
with antibody (1 µg/mL) or isotype-matched control IgG for 18 hours
at 4°C. Immunoreactivity was visualized with Extravidin
peroxidase and diaminobenzidine staining. Local overexpression of
TIMP-3 in pig vein grafts was quantified by image analysis
within 200 µm from the luminal surface. SMCs and
endothelial cells were identified by
immunostaining with 
-smooth muscle cell actin for
SMCs (human and pig tissue) or QBend10 (human; Dako) and DBA lectin
(pig vein grafts; Vector Laboratories) for endothelial
cells.
Evaluation of MMP Inhibition
Veins were analyzed for
gelatinolytic activity by gelatin in situ
zymography as described previously.23 Briefly, frozen
sections (4 sections per sample, n=3 grafts per group) were coated with
LM-1 photographic emulsion (Amersham International) diluted 1:2 with
incubation medium (50 mmol/L Tris-HCl, 50 mmol/L NaCl,
10 mmol/L CaCl2, 0.05% [wt/vol] Brij 35,
pH 7.6). After incubation overnight (human) and for 4 hours (pig) at
37°C, slides were developed and fixed. Controls included 20
mmol/L EDTA or 200 nmol/L MMP inhibitor Ro 31-9790 (Roche
Diagnostics Ltd).
Detection of Apoptosis
Three independent methods were used to evaluate
apoptosis in human veins (n=6) and pig vein grafts (n=4 per
group). First, in situ end-labeling (ISEL) was performed. In brief,
paraffin sections were washed twice in 1xTE (10 mmol/L Tris-HCl,
1 mmol/L EDTA, pH 8.0) and incubated in 50 mmol/L Tris-HCl,
pH 7.2, 10 mmol/L MgSO4, 0.1 mmol/L
dithiothreitol, 0.01 mmol/L each of dATP, dCTP, and dGTP,
0.01 mmol/L biotin-dUTP, and 8 U/mL of DNA polymerase I (Klenow).
Incorporated biotin-dUTP was detected with Extravidin peroxidase and
counterstained with hematoxylin. Second, terminal dUTP nick
end-labeling (TUNEL) was performed as described.24
Sections were incubated in 100 mmol/L cacodylate (pH 6.4), 1
mmol/L CoCl2, 0.1 mmol/L dithiothreitol,
0.01 mmol/L each of dATP and biotin-dUTP, and 8 U/mL terminal
deoxynucleotidyl transferase at 37°C for 60
minutes. Third, immunocytochemical staining for the
proapoptotic bcl-2 family member, bak, was performed.
Frozen sections were stained with a monoclonal anti–human bak antibody
(1 µg/mL) overnight at 4°C, and cytoplasmic staining was
evaluated.
Measurement of Neointima Formation
In human veins, neointima formation was quantified
from sections (n=6 per group) stained with Miller’s elastic van Gieson
(EVG) and Mayer’s hematoxylin and eosin stains25 by use
of image analysis (Image-Pro Plus version 3, Media
Cybernetics).17 18 Neointimal area was
measured in each of 3 pairs of serial sections, and the mean
neointima thickness was determined by dividing by the
length of the vein segment. The total number of neointimal
cells 7 and 14 days after infection was counted and the mean calculated
for each vein segment. The mean was divided by the length of the vein
segment in millimeters to normalize for variations in the vein diameter
between patients. Proliferation was assessed by continuous labeling
with 10 µmol/L bromodeoxyuridine (BrdU) and immunocytochemical
detection of positive nuclei as described.17 In pig vein
grafts, 4 transverse sections at each of 3 equally spaced intervals
were stained with EVG (n=6 grafts per group). For each section, the
neointimal luminal surface, internal elastic lamina, and
external elastic lamina were identified and traced from digital images,
and neointimal and medial areas were calculated.
Endothelial cell coverage was also quantified. For
human saphenous veins, the number of cells positive for the
endothelial cell marker QBend10 was counted (n=6 per
group) and expressed per millimeter of vein length. In pig vein grafts,
the percentage luminal coverage was calculated by image
analysis after DBA lectin staining (n=4 per group).
Statistical Analysis
Analysis was performed by 2-way ANOVA for multiple
comparisons between groups. Values were considered significant at
P<0.05. Values are expressed as the mean±SEM.
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Results |
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Adenovirus-Mediated Gene Transfer to Porcine Saphenous Vein
Adenovirus-mediated gene transfer to human saphenous vein has been described.18 We therefore initially characterized gene transfer to pig saphenous vein after graft placement in vivo. At 7 days after grafting, widespread ß-galactosidase staining was observed throughout the surface of the graft, with no staining in the adjacent carotid artery (Figure 1
). No staining
was observed in vein grafts treated with vehicle alone. Quantification
on cross sections revealed that 40±18% of surface cells were
ß-galactosidase–positive at 7 days (Figure 1; n=3), similar
to the infection efficiency of human saphenous vein.18
However, analysis of grafts 28 days after infection
demonstrated that only sporadic ß-galactosidase–positive cells
remained (data not shown).
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Recombinant TIMP-3 Localizes to the ECM
Unlike TIMP-1 and -2, TIMP-3 is normally found within the
ECM.26 Uninfected and RAdlacZ-infected
human saphenous veins showed low levels of TIMP-3 located within the
ECM of the media and neointima, and this was not increased
with culture, consistent with previous observations (Figure 2A and 2C; RAd35-infected not
shown).27 Infection with RAdTIMP-3 led to a substantial
increase in TIMP-3 located within the ECM at the luminal surface and in
the upper media (Figure 2B and 2D). Similar patterns were
observed in pig vessels. TIMP-3 was undetectable in control carotid
artery and in ungrafted saphenous vein (not shown). Low-level, diffuse
TIMP-3 staining throughout the neointima, media, and
adventitia was detected in vehicle- and RAdlacZ-treated
control vein grafts at days 7 and 28 (Figure 2E and 2G). In
contrast, high levels of TIMP-3 were observed in the ECM surrounding
cells of RAdTIMP-3–treated vein grafts after 7 days (Figure 2F), which was still evident at 28 days after infection, albeit
reduced (Figure 2H). Quantification of TIMP-3 overexpression by
image analysis revealed that 26.5±7.0% of the luminal surface
and upper media was immunoreactive for TIMP-3 (versus 2.2±0.7% for
vehicle-treated and 0.7±0.2% for RAdlacZ-infected
controls, P<0.05 versus both controls, n=3), which remained
elevated at 28 days after infection (11.2±2.5%). In contrast, TIMP-2
overexpression, like ß-galactosidase in
RAdlacZ-treated grafts, was evident at day 7 but not at
day 28 (not shown).
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TIMP-2 or -3 Overexpression Potently Inhibits MMP Activity
Elevated levels of pro-MMPs and activated gelatinases
(MMP-2 and -9) are associated with the progression of vein graft
neointima formation. Low-level MMP activity was detected in
control uninfected human saphenous veins, consistent with
previous observations,27 which increased with culture both
in the media and in the neointima (Figure 3A and 3C). Overexpression of TIMP-3
substantially reduced gelatinase activity both at the luminal surface
and in the medial layer (Figure 3B and 3D). MMP activity was
greatly diminished even in regions with no detectable recombinant
TIMP-3 immunoreactivity, ie, deeper medial layers. Zymography of tissue
extracts revealed that TIMP-3 overexpression did not alter the absolute
levels of MMP-2 or -9.
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Low-level MMP activity was detected in ungrafted pig saphenous
vein but was undetectable in control carotid arteries (not shown).
Evaluation of vehicle- and RAdlacZ-treated veins
revealed that MMP activity was high at day 7 after grafting both at the
luminal surface and in the media (Figure 3E
and 3F), and this
was sustained at day 28 (not shown). Overexpression of TIMP-2 or TIMP-3
reduced MMP activity throughout the neointima and media 7
days after infection (Figure 3G and 3H) and was sustained at day
28 (not shown). Adventitial MMP activity was detectable, but low, in
control vein grafts at days 7 and 28 and was unchanged by luminal
overexpression of TIMP-2 or TIMP-3 (not shown).
Localized TIMP-3 but Not TIMP-2 Overexpression Promotes
Apoptosis
To determine whether TIMP-3 overexpression promoted
apoptosis, ISEL, TUNEL, and immunocytochemical staining for bak
were performed. The numbers of ISEL-positive cells was low in control
uninfected human veins in the neointima and in the media
after 7 and 14 days (Figure 4A, Table 1). In contrast, in RAdTIMP-3
infected veins, both neointimal and medial cell
apoptosis was significantly elevated from control values
(Figure 4B, Table 1). Similar results were obtained with
the TUNEL technique (Table 1) and by immunocytochemical staining
for cytoplasmic bak (Figure 4C and 4D, Table 1).
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In pig vessels, no apoptosis was observed in control carotid
artery or control ungrafted saphenous vein (not shown). ISEL showed
that apoptosis in the neointima and media (combined
score) was moderately induced in 7-day vein grafts (0.7±0.4% for
vehicle-treated and 0.3±0.1% for RAdlacZ-treated,
Figure 3E and 3F). Grafts infected with RAdTIMP-3 (4.5±1.1%)
but not TIMP-2 (0.7±0.2%) showed significantly elevated levels of
apoptosis (Figure 4; TIMP-2 not shown),
P<0.05 versus both vehicle- and
RAdlacZ-treated control groups, n=6). Colocalization
studies revealed that 79±3% of ISEL-positive cells also stained for
-smooth muscle actin (Figure 4F, inset). Similar significant
inductions in apoptosis were obtained with TUNEL (not shown)
and immunocytochemistry for bak (Figure 4G and 4H).
Apoptosis was undetectable in 28-day vein grafts (not
shown).
Overexpression of TIMP-3 Inhibits Neointima Formation
in Human and Pig Models
TIMP-3 significantly inhibited neointima formation at
both days 7 (86%) and 14 (83%) after infection compared with
uninfected controls (Figure 5, Table 2). Similarly, the number of
neointimal cells per mm was significantly reduced in
the RAdTIMP-3–treated group at both 7 and 14 days after infection,
despite an increase in the neointimal proliferation index
after 14 days (Table 2). No effect of TIMP-3 overexpression on
medial cell density, medial proliferation rates, or
endothelial cell coverage was observed (Table 2).
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Control 28-day pig vein grafts (vehicle alone) had a consistent
and pronounced neointima consisting mainly of
-actin–positive cells (Figure 6a). No
effect on neointima formation was observed by infection
with RAdlacZ (3.9±0.5 mm2
for vehicle-treated and 4.8±1.1 mm2 for
RAdlacZ-treated vein grafts, n=6; Figure 6a, 6b, and 6e). In contrast, RAdTIMP-3 infection reduced neointima
formation significantly, by 58% (2.0±0.1
mm2, P<0.05, n=6 for
RAdTIMP-3–infected; Figure 6d and 6e) without affecting
proliferation rates or endothelial cell coverage in day
7 or day 28 vein grafts (not shown). Surprisingly, when we investigated
the effect on neointima formation of RAdTIMP-2 infection in
the pig model, it was significantly less than that of TIMP-3
(6.5±1.0 mm2, P<0.05, n=6;
Figure 6c and 6e). No effect of RAdTIMP-3 on medial
cross-sectional area was observed (7.1±1.2, 9.9±1.8, and
8.7±1.5 mm2 for vehicle-,
RAdlacZ-, and RAdTIMP-3–infected vein grafts, n=6;
Figure 6f). Hence, intimal/medial ratio was also significantly
reduced by TIMP-3 overexpression (Figure 6g).
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Discussion |
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In an attempt to inhibit the progression of neointima formation associated with late vein graft failure, we have focused on the ability of TIMP-3 to inhibit MMP activity and promote apoptosis when overexpressed.20 To accomplish this, we used adenoviral gene transfer in 2 established models of neointima formation, namely human saphenous vein organ cultures and pig saphenous vein–to–carotid artery interposition grafts. TIMP-3 was substantially overexpressed within the ECM at the luminal surface and in the upper media. MMP activity was inhibited throughout the veins, and apoptosis was induced, especially in regions of vein grafts with high TIMP-3 immunoreactivity. TIMP-3 overexpression significantly reduced neointima formation in human and pig models.
The immunolocalization of TIMP-3 is consistent with the ability of TIMP-3 to bind to the ECM.26 TIMP-3 secreted from locally infected cells therefore binds tightly to the ECM surrounding cells at the luminal surface and in the upper media, but not substantially within the ECM of distant sites. This pattern of expression may be advantageous in the context of inhibition of neointima formation as ECM localization induces high local concentrations of the inhibitor, even in the ECM surrounding noninfected cells.
In situ zymography demonstrated the pattern of gelatinase activity in pig interposition vein grafts and its inhibition by TIMP-2 or TIMP-3 overexpression. Control pig carotid arteries had no detectable MMP activity, in agreement with findings in nondiseased human arteries.28 Low-level MMP activity, however, was detected in control saphenous vein, and this substantially increased after grafting in all areas of the graft, analyzed at day 7, in agreement with results on cultured human veins.27 MMP activity was still detected at day 28, albeit reduced and mainly restricted to the neointima. Overexpression of TIMP-2 or TIMP-3 inhibited MMP activity throughout both human veins in culture and pig veins in vivo, which demonstrates a substantial bystander effect, because only luminally exposed cells were transduced. TIMP-3 inhibition of MMPs in deeper regions of human and pig veins could occur if soluble TIMP-3 is produced after high-level overexpression, as occurs in isolated cultures.21 Under these circumstances, ECM binding of TIMP-3 may become saturated by overexpression, resulting in the generation of local levels of a soluble form of TIMP-3. Alternatively, matrix-bound TIMP-3 may act as an immobilized sink for freely released MMPs.
In direct contrast to TIMP-3, TIMP-2 failed to induce apoptosis and inhibit neointima formation in pig vein grafts in vivo. We have previously reported that overexpression of TIMP-2 inhibits neointima formation in human saphenous veins solely through inhibition of MMP activity.17 However, studies in the rat carotid artery balloon angioplasty model have demonstrated that adenovirus-mediated overexpression of TIMP-2 (or use of synthetic MMP inhibitors) blocked early migration of SMCs, although a "catch-up" effect prevented inhibition of neointima formation at later points.19 29 Our data here for TIMP-2 similarly indicate that the short-term overexpression of TIMP-2 achievable with first-generation adenoviruses is not sufficient to inhibit neointima formation in vivo. The ability of TIMP-3 to bind to the ECM prolongs its retention in the neointima even when adenovirus-mediated expression declines. This, together with the dual effect of MMP inhibition and induction of apoptosis by TIMP-3, allows effective inhibition of neointima formation in vein grafts in vivo.
Together, our data demonstrate that overexpression of TIMP-3 inhibits neointima formation in human saphenous veins in organ culture and in pig interposition grafts in vivo. The ability of TIMP-3 to inhibit MMPs and promote apoptosis, together with the bystander effect resulting from its secretion and binding to the ECM, makes TIMP-3 a highly attractive candidate for gene therapy for vein graft neointima formation.
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Acknowledgments |
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This study was supported by the British Heart Foundation, the Medical Research Council for the UK, and the Garfield Western Foundation. We thank Jason Johnson, Catherine Keen, and Marcy Wyatt for technical assistance.
Received May 12, 1999; revision received July 28, 1999; accepted August 4, 1999.
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