CLINICAL STUDY
Arterial repair after stenting and the effects of gm6001, a matrix metalloproteinase inhibitor
Chris Li, MD*,
Warren J. Cantor, MD, FACC*,
Nafiseh Nili, PhD*,
Ranga Robinson, PhD*,
Louis Fenkell, BSc*,
Yen L. e Tran, BSc*,
Heather A. Whittingham, MSc*,
Winston Tsui, MD*,
Asim N. Cheema, MD*,
John D. Sparkes, MSc*,
Kenneth Pritzker, MD ,
Daniel E. Levy, PhD and
Bradley H. Strauss, MD, PhD, FACC*,*
* Roy and Ann Foss Interventional Cardiology Research Program, Terrence Donnelly Heart Center, St. Michael’s Hospital, Toronto, Canada
Department of Laboratory Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Canada
Glycomed, Incorporated, Alameda, California, USA
Manuscript received September 18, 2001;
revised manuscript received February 20, 2002,
accepted March 6, 2002.
* Reprint requests and correspondence: Dr. Bradley H. Strauss, St. Michael’s Hospital, 30 Bond Street, Toronto, Ontario, Canada M5B 1W8.
straussb{at}smh.toronto.on.ca
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Abstract
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OBJECTIVES: This study compared the extracellular matrix (ECM) and cellular responses after stenting to balloon angioplasty (BA) and to determine the late effects of matrix metalloproteinase (MMP) inhibition on arterial repair after stenting.
BACKGROUND: Although stenting is the predominant form of coronary intervention, there is limited understanding of the early and late arterial response.
METHODS: In a double-injury rabbit model, adjacent iliac arteries in 87 animals received BA (3.0 mm diameter) or stenting (3.0 mm NIR). Rabbits were treated for 1 week postprocedure with either GM6001 (100 mg/kg per day), an MMP inhibitor or placebo and sacrificed at 1 week or at 10 weeks’ postprocedure. Arteries were analyzed for morphometry, collagen content, gelatinase activity, cell proliferation and DNA content.
RESULTS: Stented arteries had significant increases in collagen content (2-fold) at 10 weeks compared to BA-treated arteries. At one week, overall gelatinase activity was increased >2-fold in stented arteries, with both 72 kD and 92 kD gelatinase activity. Stented arteries also had increases in both intimal DNA content (1.5-fold) and absolute cell proliferation (4-fold). Compared to placebo, GM6001 significantly inhibited intimal hyperplasia and intimal collagen content, and it increased lumen area in stented arteries without effects on proliferation rates.
CONCLUSIONS: Stenting causes a more vigorous ECM and MMP response than BA, which involves all layers of the vessel wall. Inhibition by MMP blocks in-stent intimal hyperplasia and offers a novel approach to prevent in-stent restenosis.
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Abbreviations and Acronyms
| | ANOVA | | analysis of variance | | BA | | balloon angioplasty | | BrdU | | bromodeoxyuridine | | CSA | | cross-sectional area | | ECM | | extracellular matrix | | HPF | | high power field | | IVUS | | intravascular ultrasound | | MMP | | matrix metalloproteinase | | MMPI | | matrix metalloproteinase inhibitor | | SMC | | smooth muscle cell |
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The last 10 years have witnessed tremendous growth in percutaneous interventions for symptomatic coronary artery disease, with more than one million procedures performed worldwide in 1998 (1). In most centers, stents are used in >80% of interventional procedures, as they provide both a more reliable immediate result and improved restenosis rates compared with balloon angioplasty (BA) (2,3). Nevertheless, in-stent restenosis persists as a significant limitation of this procedure, which is particularly resistant to reintervention (4). Despite the widespread utilization of stents, only a limited understanding of the arterial response to stenting has been achieved. Previous work from our group has highlighted the role of collagen turnover in the arterial response to BA injury and the importance of matrix metalloproteinase (MMP) expression as a mediator of the extracellular matrix (ECM) response (5,6). Moreover, we have shown that administration of the nonspecific MMP inhibitor (MMPI), GM6001, causes a significant decrease in both collagen synthesis and collagen content at one week after balloon injury that was associated with a 25% reduction in intimal hyperplasia (6). Recently, other MMPIs reduced late constrictive remodeling but not intimal hyerplasia after balloon injury in a porcine model (7,8). However, a different MMPI failed to prevent constrictive remodeling or intimal hyerplasia in balloon-treated and stented arteries in a primate model (9). The main objectives of this study were to compare the early and late effects of stenting and BA on arterial repair, with a particular emphasis on the ECM response, and specifically, to assess the effects of an MMPI on in-stent intimal hyerplasia. An important aspect of these studies was to elucidate the effects of GM6001, a nonspecific MMPI, on collagen synthesis in cultured smooth muscle cells (SMCs) as well as collagen accumulation in the vessel wall after stenting.
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Materials and methods
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The model.
The animal experiments were performed in accordance with guidelines set out by the University of Toronto and approved by the St. Michael’s Hospital Animal Care Committee. A double-balloon normolipemic injury model was used in 87 male New Zealand White rabbits weighing 3.6 to 3.8 kg, as previously described (5,6). Angioplasty and stenting of the iliac arteries were performed three weeks following the initial procedure. A 16-mm length, 3.0-mm diameter premounted NIR stent (Boston Scientific, Natick, Massachusetts) was deployed randomly into either the left or right iliac artery using two 40-s inflations, initially at 8 atms and then at 10 atms. The BA catheter was then repositioned at the same level in the contralateral iliac artery, and four one-min inflations were done (6, 8, 4 and 10 atms). To determine the acute results on lumen area, intravascular ultrasound (IVUS) examination was done immediately after the BA/stenting procedure in 11 rabbits using either a 2.9F (Ultracross, Boston Scientific) or 2.6F (Discovery, Boston Scientific) IVUS catheter. Following intra-arterial nitroglycerin (50 µg), a manual pullback was performed and images from the proximal, mid- and distal-treated arterial segment were recorded on VHS tape. Images were analyzed off-line. All animals were pretreated with 80-mg aspirin daily, starting one day before the procedure, and continued for two weeks.
To assess the effects of MMP inhibition, animals were given daily injections of either vehicle ("placebo group") or GM6001 (Glycomed, San Francisco, California, 100 mg/kg per day as subcutaneous suspension), beginning one day before the second injury until seven days after the procedure (6). GM6001 is a nonspecific hydroxamic acid-based MMPI with potent inhibitory activity against collagenase, gelatinases and stromelysin (10). Animals were euthanized at either 1 week or 10 weeks after the second injury (Fig. 1). For biochemical studies, iliac artery tissue was removed under general anesthetic, followed by a fatal intracardiac injection of thiopentol. For histomorphometric studies, iliac arteries were perfusion-fixed in 10% buffered formalin for 20 min at a perfusion pressure of 80 mm Hg.
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Figure 1 Schematic diagram outlining study protocol. BA = balloon angioplasty; MMP = matrix metalloproteinase.
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Morphometry.
The BA-treated and stented arteries were embedded in paraffin and Spurr resin (Marivac, Halifax, Canada), respectively. Cross sections were obtained from three different sites (proximal, mid and distal). In the stented segments, injury scores were assessed according to Schwartz et al. (11). Computer-assisted morphometry was performed to determine lumen cross-sectional area (CSA), and intimal CSA on elastic trichrome-stained slides using an image analysis software program (Scion Image, Scion, Frederick, Maryland).
Ex vivo collagen measurements.
The medial/adventitial layers were manually separated from the intimal layer in both the stented and contralateral BA-treated arterial segments and analyzed separately for collagen content using a previously described method (5). The adequacy of the separation of the vessel wall layers was confirmed by histologic examination of arterial tissue. An additional six uninjured iliac arteries were also analyzed for collagen synthesis and content.
Cell proliferation.
Bromodeoxyuridine (BrdU, Sigma), 300 mg, a thymidine analogue, was injected subcutaneously in six placebo-treated animals at 24 h and 12 h before sacrifice at one week. A biotinylated mouse anti-BrdU antibody clone BR-3 (Caltag Laboratories, Burlingame, California) was used as the primary antibody at a dilution of 1/50 for paraffin (balloon-treated) sections, and 1/300 for plastic (stented) sections. The arterial cross section with the maximal intimal hyperplasia was selected for BrdU quantification. Total labeled cells were counted using an image analysis system (Scion Image, Scion) under 20x magnification. The BrdU incorporation was assessed in the entire arterial segment for balloon-treated arteries and in peri-strut regions and also between struts for stented vessels (12). Data were expressed as absolute cell proliferation (total labeled cells/cross section) and with a correction for intimal area.
Cell density.
The numbers of nuclei in the intimal layer were counted under 40x magnification at four separate sites (two cross sections/vessel). Data were expressed as nuclei/high power field (HPF).
Dna content.
The DNA was measured separately in the intima and medial/adventitial layers in five stented and five balloon-treated arteries (8-mm segment length) using the DNeasy kit (Qiagen, Valencia, California) according to the manufacturer’s instructions.
Gelatinase activity assays.
Gelatin zymography was performed as previously described (6). Gelatinases were also measured with a quantitative fluorescence gelatinase assay that used a gelatin-fluorescein conjugate as a substrate (EnzChek gelatinase assay, Molecular Probes, Eugene, Oregon). For this assay, arterial samples were extracted in MMP assay buffer (50 mM Tris-HCl; 150 mM NaCl; 5 mM CaCl2; 0.2 mM sodium azide, pH 7.6) containing 10 mg/ml leupeptin and 1 mM phenylmethyl sulfonyl fluoride, then partially purified by ammonium sulfate precipitation and dialyzed.
In vitro collagen synthesis.
Primary cultures of rabbit aortic SMCs were grown to 80% confluency and made quiescent in serum-free medium for 24 h. The medium was replaced with fresh serum-free medium with or without GM6001 and incubated for 24 h. Ascorbic acid (50 µg/ml) and 14C-proline (5 µCi/ml) were added to the cells 6 h before harvesting. A bacterial collagenase digestion method was used to determine the rate of collagen synthesis in the conditioned medium (13). Experiments were done in triplicate on three separate occasions.
Statistics.
Data are expressed as mean ± SEM. In placebo-treated animals, paired Student t tests were used to compare results of gelatinase activity, cell proliferation, and DNA content in stented and balloon-treated arteries at one week. A two-way analysis of variance was performed using SAS (version 6.12, mixed procedure) to compare in separate analyses assay results for IVUS, histology, collagen content and tissue wet weight from the two procedure groups at 10 weeks (stents and balloon-treated arteries) and the two treatment groups (GM6001 and controls). To adjust the significance tests for multiple comparisons, p values of  0.01 were considered statistically significant (14).
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Results
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Differences between stent and balloon-treated arteries in placebo rabbits.
Immediate postprocedural results.
In vivo measurements of lumen size by IVUS immediately after the stent and angioplasty procedure showed a significant 50% acute increase in lumen CSA of stented arteries compared to BA-treated arteries (5.27 ± 0.12 mm2 vs. 3.57 ± 0.34 mm2, p < 0.002).
Morphometric measurements at 10 weeks
At 10 weeks, the intimal CSA of stented arteries was  2.5-fold higher than BA-treated arteries (0.95 ± 0.06 mm2 vs. 0.40 ± 0.07 mm2, p < 0.0001).
Collagen content and tissue wet weights
At one week there was a significant increase in intimal collagen content (35 ± 3 µg vs. 22 ± 3 µg hydroxyproline/arterial segment, p = 0.006) in stented versus BA-treated arteries (Fig. 2). By 10 weeks, there was a significant, approximately 2-fold increase in intimal and medial/adventitial collagen content in stented compared to BA-treated arteries. Uninjured iliac arteries had similar medial/adventitial collagen as balloon-treated arteries at 10 weeks (180 ± 39 µg vs. 198 ± 19 µg hydroxyproline/arterial segment, p = NS). These increases in collagen content in stented vessels at 10 weeks were also associated with increases in tissue wet weight in the intima (23.8 ± 1.6 vs. 9.4 ± 1.0 mg/arterial segment, p < 0.0001) and the media/adventitia (53.7 ± 4.0 vs. 23.8 ± 2.5 mg/arterial segment, p < 0.0001).
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Figure 2 Collagen content in the intima (left) and media/adventitia (right). Stented arteries had significant increases in collagen content in the intima at 1 week and 10 weeks and in the media/adventitia at 10 weeks, compared to balloon angioplasty (BA)-treated arteries. +p = 0.006; *p < 0.002.
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Dna content and cell proliferation
There was a 50% increase in intimal DNA content in stented arteries compared to BA-treated arteries (5.76 ± 0.66 vs. 3.83 ± 0.48 µg/arterial segment, p = 0.045) at one week. In the medial/adventitial layer, there was also a nonsignificant increase in DNA content in stented arteries (6.71 ± 1.42 vs. 3.48 ± 0.77 µg/arterial segment, p = 0.081). In stented vessels, the BrdU-labeled cells were predominantly located in the peri-strut region. At one week following the second injury, there was a 4-fold increase in absolute cell proliferation in the arterial wall in stented compared to BA-treated arteries (1,141 ± 216 vs. 288 ± 175 BrdU-labeled cells/cross section, p = 0.011). However, when values were corrected for intimal area, no significant differences existed.
Gelatinase activity
At one week, gelatin zymography demonstrated prominent 72 kD and 62 kD bands consistent with pro- and active forms of MMP-2 in both stented and BA-treated arteries (Fig. 3). A 92 kD band (MMP-9) was much more prominent in stented than in BA-treated arteries. In the fluorescence assay, there was a >2-fold increase in overall gelatinase activity in stented compared to BA-treated arteries (1.04 ± 0.35 vs. 0.44 ± 0.20 U/artery, p < 0.006).
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Figure 3 Gelatin zymogram in balloon angioplasty (BA)-treated and stent arteries. Conditioned medium from chondrocyte cultures were run as positive controls to show 92 kD and 72 kD gelatinolytic activity, which was confirmed by molecular weight markers (not shown). In both BA-treated and stent arteries, 72 kD and 62 kD gelatinolytic bands are evident, corresponding to the pro- and active forms of matrix metalloproteinase (MMP)-2. In stented (but not BA-treated) arteries, an additional gelatinolytic band at 92 kD is evident, corresponding to MMP-9 activity.
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In vitro effects of gm6001, an mmpi
GM6001 caused a dose-dependent decrease in collagen synthesis in cultured SMCs, with a 95% reduction at 1.0 µM (Fig. 4).
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Figure 4 Collagen synthesis in cultured smooth muscle cells showed a dose-related inhibition with GM6001. There is >95% inhibition at 1.0 µM. CPM = counts per minute.
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In vivo effects of gm6001
GM6001 significantly decreased intimal CSA at 10 weeks in stented arteries (0.67 ± 0.06 mm2 vs. 0.95 ± 0.06 mm2, p < 0.003) compared to placebo (Figs. 5 and 6). This was accompanied by an increase in stent lumen CSA at 10 weeks in GM6001-treated animals compared to placebo (5.21 ± 0.17 mm2 vs. 4.58 ± 0.16 mm2, p = 0.016, Fig. 6). No significant differences were seen in mean or maximum injury scores in stented arteries in placebo-treated animals. In balloon-treated arteries, there was a nonsignificant decrease in intimal CSA in GM6001-treated arteries compared to placebo-treated arteries (0.24 ± 0.06 vs. 0.40 ± 0.07, p = 0.070).
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Figure 5 Representative photomicrograph of elastic trichrome-stained cross sections of stented arteries showing increased intimal hyerplasia in a placebo-treated artery (A) compared to a GM6001-treated animal (B). 10x objective. I = intima; L = lumen; S = stent strut.
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Moreover, GM6001 significantly decreased intimal collagen content at 10 weeks in stented arteries (57 ± 8 µg vs. 105 ± 10 µg hydroxyproline/arterial segment, p = 0.0002) compared to placebo (Fig. 6). This was associated with a significant reduction in intimal wet weight from 23.8 ± 1.6 mg to 13.0 ± 1.5 mg (p < 0.0001). There were no significant effects of GM6001 on medial/adventitial collagen content (data not shown).
At one week following the second injury, no significant differences existed in cell proliferation in GM6001-treated (n = 5) animals compared to placebo-treated (n = 5) animals in stented arteries (1,117 ± 286 vs. 1,041 ± 119 BrdU-labeled cells/mm2 intimal area, GM6001 and placebo, respectively). At 10 weeks, there were no significant differences in mean cell density in stented arteries (104 ± 21 vs. 122 ± 26 nuclei/HPF, GM6001 and placebo, respectively).
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Discussion
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Previous work from our group has shown that ECM is an important aspect of arterial repair following balloon injury (5,6). We now report that stenting causes a marked increase in collagen accumulation, and that this matrix response and the extent of intimal hyerplasia can be significantly inhibited by a relatively brief (one week) exposure to an MMPI. Though increases in cell proliferation after stenting have been reported (12), this is the first detailed report of ECM changes after stenting. The enhanced collagen response in stenting, particularly in the intimal layer, may be due to several factors, including increased cell number, the pronounced and prolonged inflammatory response associated with a "foreign body" and the stimulatory effects of persistent stretch on the vessel wall. Several in vitro and in vivo studies have demonstrated that mechanical strain such as cyclic stretching stimulates collagen synthesis in vascular SMCs and the arterial wall (13,15–18). Angiographic human coronary artery studies have shown that, due to the scaffolding properties of stents, there is a 40% to 50% acute increase in lumen diameter in stented compared to balloon-treated arteries (2,3). Our IVUS results also showed increased stretch in the stented arteries, with a significant 50% acute increase in lumen CSA of stented arteries compared to BA-treated arteries. Thus, the persistent stretch in stented arteries may be a potent stimulus for ongoing collagen synthesis and increased collagen accumulation in the arterial wall.
Gelatinase activity.
Stenting resulted in a 2-fold increase in overall gelatinase activity/arterial segment compared to BA. The gelatin zymograms demonstrated a unique pattern of gelatinase activation after stenting, confirming the recent observations of Feldman et al. (19). The presence of 92 kD gelatinolytic activity (presumably MMP-9) in stented but not BA-treated arteries may be due to more robust and persistent macrophage infiltration early after stenting compared to BA (19–21).
Effects of mmpi.
The most novel and important finding of this study is that the nonspecific MMPI GM6001 resulted in a persistent and potent significant inhibition of intimal hyperplasia and an increase in lumen area in stented arteries. Several mechanisms may be contributing, including significant inhibition of intimal collagen accumulation demonstrated in this study, as well as a reduction in cellular migration into the intima after arterial injury (22,23). The latter mechanism may explain why cell density was not altered in GM6001-treated arteries in this study despite the reduction in collagen content. There is no convincing evidence from this study or previous studies that MMPIs affect cell proliferation in either stented or BA-treated arteries (6,22,23).
It may seem paradoxical that an agent that inhibits matrix-degrading enzymes resulted in decreased collagen content. There are several potential reasons. Collagen degradation products have some detrimental effects that contribute to restenosis. These degradation products are chemotactic for inflammatory cells and fibroblasts that are intricately involved in neointimal formation (24,25). Collagen degradation enhances SMC migration, probably by exposing cryptic RGD sequences, which allow binding to alphav-beta3 integrin receptors that promote migration (26). In contrast, intact (i.e., nondegraded) fibrillar type I collagen inhibits SMC proliferation by regulating cell cycle events, including cyclin E–associated kinase and cyclin–dependent kinase-2 phosphorylation (27). Thus, MMPIs, by virtue of blocking the formation of collagen degradation products, can have favorable effects on vessel repair.
In addition, we have previously shown that the MMPI GM6001 decreased in vivo collagen synthesis and collagen content at one week after vessel wall injury (6). In skin-wound models, GM6001 also decreased collagen content, collagen type I gene expression and epidermal hyperplasia (28,29). In our study, we show a potent inhibitory effect of GM6001 on collagen synthesis in cultured SMCs. Thus, MMPs also appear to be involved in the process of collagen synthesis. This can be explained by in vitro studies showing that MMP inhibition, either by a nonspecific MMPI, batimastat, or by antisense oligonucleotides directed against MMP-3 mRNA, can prevent phenotypic modulation and activation of vascular SMCs (30,31). Also, MMPIs have several anti-inflammatory properties that may contribute to a decrease in collagen synthesis (32–34).
Based on the pattern and extent of gelatinase activity and the response to the MMPI, our results suggest that MMPs play a more critical role in intimal hyperplasia formation after stenting compared to balloon injury. Our results are the first report of a significant inhibitory effect of a MMPI on in-stent intimal hyerplasia and in-stent collagen accumulation. In contrast to our findings, Cherr et al. (9) recently failed to demonstrate an inhibitory effect of a different MMPI (RO11302908) in a monkey iliac artery stent model. In addition, their study showed no effect on constrictive remodeling after angioplasty, which differs from the results of two separate studies of another MMPI in the porcine coronary angioplasty model (7,8). Of note, RO113-2908 has significantly less potency in inhibiting MMP-1 than GM6001 [IC50 in nmol/l: 360 (9) vs. 0.18 (10)].
Another potential factor that should be considered is the differences in models. Cherr et al. (9) used a high cholesterol diet model with extremely high total plasma cholesterol (>10 mmol/l) and low density lipoprotein (>9 mmol/l) levels. We did not use a hypercholesterolemic diet in our model. There were also differences between the studies in the method of MMPI administration. Because the rabbit iliac model, like all animal models, differs in several respects from human atherosclerotic coronary arteries, caution should be used in extrapolating these results to the human coronary setting. Currently, MMPI-coated stents are being evaluated in human coronary clinical trials (Brilliant and Batman studies).
Conclusions.
In summary, stents result in a more vigorous ECM and cellular response than BA alone. Administration of an MMPI, by reducing intimal collagen accumulation and intimal hyperplasia in stented arteries, represents a novel therapeutic strategy to prevent in-stent restenosis.
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Acknowledgments
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We gratefully acknowledge the excellent technical work of Larissa Chestapolova, Maria Mendes, Theodora Venetis and Kelvin So.
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Footnotes
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This work was supported by the Medical Research Council of Canada and is dedicated to the memory of Robyn Strauss Albert.
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S. Janssens and H. R. Lijnen
What has been learned about the cardiovascular effects of matrix metalloproteinases from mouse models?
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A. P. Wong, N. Nili, and B. H. Strauss
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G. Pasterkamp, M. J. Sierevogel, D. P.V. de Kleijn, B. H. Strauss, R. L. Geary, and G. S. Cherr
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Top
Abstract
Materials and methods