doi: 10.1161/hc3801.095661
(Circulation. 2001;104:1538.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Short-Term Local Delivery of an Inhibitor of Ras Farnesyltransferase Prevents Neointima Formation In Vivo After Porcine Coronary Balloon Angioplasty
From the Department of Physiology and Pharmacology, University of Strathclyde, and Department of Pathology, Glasgow Royal Infirmary (A.R.M.), Glasgow, Scotland, UK. Dr Work is now at the Department of Medicine and Therapeutics, Western Infirmary, Glasgow.
Correspondence to Dr C.L. Wainwright, Department of Physiology and Pharmacology, University of Strathclyde, Strathclyde Institute for Biomedical Sciences, 27 Taylor St, Glasgow G4 0NR, Scotland, UK. E-mail c.l.wainwright{at}strath.ac.uk
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Abstract |
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Background— Mitogenic stimuli present at the site of coronary arterial balloon injury contribute to the progression and development of a restenotic lesion, many signaling through a common pathway involving the small G protein p21ras. Our aim was to demonstrate in biochemical studies that farnesyl protein transferase inhibitor III (FPTIII) is an inhibitor of p21ras processing and that when it is given locally in vivo at the site of coronary balloon injury in a porcine model, it can inhibit neointima formation.
Methods and Results— FPTIII (1 to 25 µmol/L) concentration-dependently reduced p21ras levels in porcine coronary artery smooth muscle cell membranes. FPTIII also prevented p42/p44 MAPK activation and DNA synthesis in response to platelet-derived growth factor in these cells at a concentration of 25 µmol/L. Application of 25 µmol/L FPTIII locally for 15 minutes to balloon-injured porcine coronary arteries in vivo prevented neointima formation assessed at 4 weeks, reduced proteoglycan deposition, and inhibited adventitial hypertrophy. Coronary arteries from FPTIII-treated pigs had no deterioration in contraction or in endothelium-dependent relaxation.
Conclusions— The study demonstrates in the pig that short-term local delivery of inhibitors of p21ras-dependent mitogenic signal transduction prevents restenosis after balloon angioplasty.
Key Words: neointima • farnesyl transferase inhibitor • arteries • angioplasty
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Introduction |
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The main mechanisms thought to underlie restenosis include smooth muscle cell (SMC) migration and proliferation, adventitial remodeling, and matrix production.1 Numerous growth factors and mitogenic autocoids that could accelerate new tissue formation and development of the restenotic lesion have been found at the site of injury.2,3 Signal transduction by these agents involves the mitogen-activated protein kinase (MAPK) pathway, and p21ras-dependent activation of p42/p44 MAPK has been demonstrated in vivo in a porcine model of balloon injury early after angioplasty.4 Moreover, the local delivery of H-ras dominant negative mutant (N17 and L61, S186) plasmid constructs5 and adenovirus-mediated transfer of dominant negative H-ras6 have both been shown to significantly reduce neointima formation in the rat carotid artery.
Farnesyl transferase (FTase) is an enzyme that catalyzes the insertion of a farnesyl moiety onto the carboxy terminus of p21ras, this being an essential step in the membrane adherence of the protein before activation of the MAPK pathway. Furthermore, FTase also catalyzes Rho farnesylation, another small-molecular-mass G protein involved in a separate pathway that plays a significant role in regulating cell proliferation. Inhibitors of FTase have been under development for applications in cancer therapy for several years7 because of their ability to prevent excessive cell growth in cancer cell lines. Inhibitors of FTase can also inhibit proliferation8,9 and migration8 of vascular SMCs in vitro. It was our hypothesis, therefore, that an inhibitor of FTase could be an appropriate means of decreasing neointima formation after balloon angioplasty. FTase inhibitors may have an advantage over existing specific gene-targeting therapies or antisense oligonucleotide therapies, because they can target both Ras- and Rho-dependent signaling.10 In this article, we focused on whether the FTase inhibitor {(E,E)-2-[2-oxo-2-[(3,7,11-trimethyl-2,6,10-dodecatrienyl)oxy]aminoethyl] phosphonic acid, (2,2-dimethyl-1-oxopropoxy) methyl ester sodium} (farnesyl protein transferase inhibitor III, FPTIII)11 acts on Ras-dependent activation of p42/p44 MAPK and blocks smooth muscle proliferation. These experiments enabled us to establish an effective concentration of FPTIII for subsequent local delivery after angioplasty in vivo to determine its effects on neointima formation and vascular function.
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Methods |
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Biochemical Studies
Porcine vascular SMCs (PVSMCs) were obtained by explantation of 5-mm coronary artery rings into 5 mL of medium (1:1 Ham’s F12 and Waymouth’s MB 752/1) containing 15% FCS and 1% penicillin-streptomycin (5000 IU/mL). Cells were used between passages 3 and 5. PVSMCs were incubated in medium containing 1% FCS for 24 hours to synchronize the cell cycle to G0. FPTIII (1 to 25 µmol/L) was added for 18 to 24 hours before stimulation with platelet-derived growth factor (PDGF) (10 ng/mL), endothelin 1 (ET-1) (100 nmol/L), phorbol 12-myristate 13-acetate (PMA) (1 µmol/L), or bradykinin (200 nmol/L). Cell lysates were analyzed for activation of p42/p44 MAPK by an in vitro kinase assay or by an electrophoretic mobility shift assay.12 Similarly, membrane-associated p21ras was detected by Western blotting. Cell proliferation was determined as PDGF-induced [3H]thymidine incorporation in the absence and presence of 1 to 25 µmol/L FPTIII.13 Shift blots of PDGF- and PMA-induced phosphorylation of p42 MAPK were also performed in the absence and presence of 1 to 25 µmol/L FPTIII, according to Conway et al.12
In Vivo Coronary Balloon Angioplasty
All experimental procedures were performed under the guidelines of the UK Home Office Scientific Procedures (1986) Act. Male Large White/Welsh Landrace pigs (n=18; 14 to 19.5 kg) were premedicated with aspirin (325 mg PO), sedated with azaperone (5 mg/kg IM), and anesthetized with a mixture of O2/halothane/nitrous oxide. An introducer sheath (7F) was inserted into the artery to allow a 6F guide catheter to be advanced to the coronary ostium. A 3-mm balloon angioplasty catheter was then advanced via the guide catheter (under fluoroscopic control) to the midpoint between the first and second diagonal branches of the left anterior descending coronary artery (LAD). After a coronary angiogram to confirm the positioning of the balloon catheter, the balloon was inflated 3 times to 10 atm, providing an approximate balloon-to-artery ratio of 2:1. In 11 pigs, immediately after withdrawal of the balloon catheter, a 3-mm Dispatch catheter (Scimed) with a double lumen was advanced to the site of balloon angioplasty to deliver either saline (vehicle; n=4) or FPTIII (25 µmol/L; n=7) over a 15-minute infusion period at a rate of 200 µL/min (total injection volume 3 mL containing 75 nmol FPTIII). The construction of this catheter essentially isolates the angioplastied segment of the artery and supplies to the luminal surface a chosen concentration of drug while permitting blood to flow through the central lumen to supply the distal tissues. After removal of all catheters, the femoral artery was permanently ligated and the wound to the leg repaired. All animals were given antibiotic (ampicillin 50 mg/kg IM) and analgesic (buprenorphine 0.5 mg IM) cover before recovery from the anesthetic. Four weeks after surgery, the pigs were euthanized with sodium pentobarbitone (70 mg/kg), the heart was removed, and both the entire LAD and left circumflex coronary artery (LCx) were dissected free. The injured section of the LAD and a segment of LCx of equivalent diameter were each cut into 4 artery rings. Two of the rings were used immediately for functional studies, with the remaining 2 rings placed into phosphate-buffered formal saline for subsequent histological analysis.
Functional Analysis
Two rings from both the LAD and LCx were mounted on intraluminal steel wires in Krebs solution aerated with 95% O2/5% CO2 at 37°C. The vessels were equilibrated at their optimum resting force of 4 g for 1 hour before repeated exposure to 40 mmol/L KCl until 2 consecutive applications resulted in identical contractions. One ring from each artery was used to construct cumulative concentration-response curves to 5-HT, phenylephrine KCl, calcimycin (A23187), and morpholinosynonimine (SIN-1). Vasorelaxant responses were determined after precontraction with 5-HT (10-6 mol/L). The remaining 2 rings were used as time-matched controls to correct relaxant responses in the case of loss of tone over the course of the experiment.
Histological Analysis and Morphometry
Fixed LAD and LCx rings were processed for histological analysis and embedded in paraffin wax. Blocks were coded by an individual with the research group until histological analysis was complete. The 4-µm sections were cut and stained with (1) hematoxylin and eosin for morphological assessment and (2) alcian blue to detect the presence of proteoglycans. Planimetry was used to determine the relative areas of the vessel layers from photomicrographs of sections from each artery. Proteoglycan deposition was quantified by 2 independent observers to estimate the percentage of positive staining within the neointima.
Materials
Unless otherwise stated, chemicals were purchased from Sigma Chemical Co. Cell culture materials were purchased from Gibco BRL Life Technologies Ltd. FPTIII was obtained from Calbiochem. Anti–ERK-2 and anti-Ras monoclonal antibodies were purchased from Affiniti. Reporter HRP-linked anti-mouse antibody was a gift from the Scottish Antibody Production Unit, Carluke. 1,4-Dithiothreitol and streptavidin-peroxidase were purchased from Boehringer Mannheim. Amersham International supplied the p42/p44 Biotrak MAPK assays, nitrocellulose membranes, enhanced chemiluminescence detection kit, methyl-[3H]thymidine, and [32P]ATP. Halothane was obtained from Mallinckrodt Veterinary and amphipen LA from Mycofarm UK Ltd.
Statistical Analysis
For the in vitro biochemical studies, values shown are the mean±SD of n experiments performed on separate cell preparations. For the p42/p44 MAPK activity assay, data were calculated as the activity in pmol · min-1 · mg-1 cell lysate protein and expressed as the fold increase above basal MAPK levels. With the [3H]thymidine incorporation assays, data were expressed as the fold increase above basal levels. Groups were compared by paired t test or 1-way ANOVA followed by Tukey’s test for multiple comparisons. For the in vivo studies, values shown are the mean±SEM of n animals. Morphological data are expressed as area (µm2) and were compared by 1-way ANOVA followed by Dunnett’s test. Concentration-response curves were compared by 2-way ANOVA followed by a Newman-Keuls post hoc test. In all cases, a value of P<0.05 was taken to indicate statistical significance.
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Results |
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Effect of FPTIII on Mitogenic Signal Transduction in Cultured PVSMCs
FPTIII concentration-dependently (1 to 25 µmol/L) reduced the p21ras levels in PVSMC membranes (Figure 1), virtually abolishing membrane association at 25 µmol/L. This is consistent with an inhibitor action at the level of FTase. In the MAPK activity assay, FPTIII inhibited responses to PDGF and endothelin but not to PMA or bradykinin (Figure 2a). This demonstrates that the effect of FPTIII is restricted to growth factors (PDGF) and Gi-coupled receptor agonists (eg, ET-1) that signal to p42/p44 MAPK via a p21ras-dependent pathway. In contrast, p42/p44 MAPK activation in response to Gq-dependent receptor agonists, such as bradykinin, and protein kinase C activators, such as PMA, is insensitive to FPTIII, because these agonists regulate p42/p44 MAPK via a Ras-independent mechanism in several cell types.14–16 Shift blots of agonist-induced phosphorylation of p42/p44 MAPK activity confirmed the differential effect of FPT on responses to PDGF and PMA (Figure 3).
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Thymidine incorporation studies also demonstrated that incubation of PVSMCs with FPTIII (25 µmol/L) for 18 to 24 hours inhibited PDGF-induced [3H]thymidine incorporation into DNA (Figure 4), providing direct evidence that FPTIII inhibits cell proliferation. Furthermore, the effect of FPTIII on PDGF-induced MAPK activity was readily reversed by 100 nmol/L farnesyl phosphate (FPP substrate for FTase and thus a competitor with FPTIII for FTase; Figure 2b), consistent with an action of FPTIII to inhibit FTase.
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Effect of FPTIII on Neointima Formation After Coronary Arterial Balloon Injury
The response to injury in control, untreated LADs was similar to that reported in previous studies17 and consisted of the development of neointimal lesions in close proximity to areas of rupture of the internal elastic lamina (IEL). The lesions contained large numbers of vascular SMCs, oriented in a longitudinal rather than circumferential pattern, covered with an intact endothelial cell layer (Figure 5b). Intense positive proteoglycan staining (Figure 5c; 50.0±6.2% of the neointima) demonstrated production of extracellular matrix. Significant neointimal formation (19.6±0.8% of total medial and intimal areas) was observed in all untreated porcine LADs. Significant adventitial thickening was also present in these arteries (Figure 6). Local application of drug vehicle (saline) to the injury site in 4 control pigs did not result in neointima that was any different in size or morphology from the rest of the control group; thus, the planimetric data from all of the control pigs were pooled. In LADs from pigs treated with 25 µmol/L FPTIII, there was marked suppression of the extent of neointima formation (Figure 5d) and no adventitial thickening (Figure 6), despite rupture to the IEL. Furthermore, significantly less (26.5±4.6%; P<0.05) positive proteo- glycan staining was present in FPTIII-treated arteries (Figure 5d).
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Effect of Balloon Injury and FPTIII Treatment (25 µmol/L) on Porcine Coronary Artery Vascular Function
Cumulative concentration-response curves to KCl, 5-HT, and phenylephrine demonstrated an enhanced response to these contractile agents in arteries injured 4 weeks previously compared with noninjured LCx rings (Figure 7a through 7c). Treatment with FPTIII at the time of injury abolished (P<0.05) the increased responsiveness to 5-HT and phenylephrine and attenuated the enhanced response to KCl. The relaxant responses of arteries precontracted with 5-HT (10-6 mol/L) to both the endothelium-dependent vasodilator (calcimycin) and the endothelium-independent vasodilator SIN-1 were not significantly impaired by injury (Figure 8), demonstrating that sufficient endothelial regrowth had occurred to restore endothelial function. Importantly, both the endothelium-dependent and -independent relaxations in FPTIII-treated arteries were also intact, demonstrating that the drug had no adverse effect on either endothelial recovery or the ability of the coronary artery to dilate.
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; n=14), untreated LAD injured 4 weeks previously (
; n=7), and injured arteries treated with FPTIII at time of injury (
; n=7). *P<0.05 vs noninjured LCx rings; #P<0.05 vs untreated injured LAD rings.
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Discussion |
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This study is the first to demonstrate that local short-term (15 minutes) application of an FTase inhibitor, targeting the critical step in adherence of p21ras to the membrane required for MAPK activation,18 prevents neointima formation after balloon angioplasty while preserving endothelial function. This is consistent with the idea that intervention at the level of p21ras processing can abolish mitogenic signal transduction in SMCs and with our observations that FPTIII abolished PDGF-induced p42/p44 MAPK activation, p21ras targeting to membranes, and thymidine incorporation in cultured porcine coronary arterial SMCs in vitro. Our findings also extend previous observations in rat and human primary cell cultures8,9 by demonstrating that FPTIII blocks the actions of agonists other than PDGF (eg, ET-1) that signal through p21ras but has no effects on agonists that use a mechanism independent of p21ras.
The primary mechanism through which FPTIII prevents neointima formation is inhibition of early proliferation of SMCs, according to the data from the thymidine incorporation studies. It is also probable, however, that migration of SMCs into the neointima may be prevented, as observed with other FTase inhibitors in cultured rat SMCs.8 The FPTIII-induced reduction in proteoglycan is most likely a consequence of the smaller neointima size, containing fewer SMCs synthesizing extracellular matrix. FPTIII, however, may also be interfering with the signaling pathway involving transforming growth factor-ß as a mediator in matrix proteoglycan synthesis,19,20 because binding of FTase to type I transforming growth factor-ß appears to be an essential step in this signaling process.21 FPTIII inhibited neointimal hypertrophy at 4 weeks after injury, which is the time of maximal neointima development in the balloon-injured pig coronary artery.17 It would be valuable to have further data with longer time points to confirm that neointima growth remains suppressed.
There are several benefits of targeting a common step in the pathways controlling cell proliferation, such as Ras processing. First, it is well recognized that the formation of a neointimal lesion is the result of a complex interplay between a range of growth stimulants. Therefore, blocking the action of one mediator is unlikely to prevent proliferation, which can be triggered by the remaining mediators. Second, FPTIII will target only those cells that are actively migrating and proliferating while, importantly, having no effect against normally functioning differentiated cells. Our results show that endothelial function after FPTIII administration is intact, suggesting a "sparing" of endothelial cell regrowth. This may offer a major advantage over other antiproliferative agents currently being investigated for use in the prevention of restenosis, because there is no evidence in the literature that these agents also spare endothelial function. A further advantage of FPTIII is the preservation of vascular function. FPTIII prevents the hyperresponsiveness to contractile agonists seen after injury while preserving normal contractile function. The presence of a neointimal lesion has been shown previously to result in enhanced sensitivity to 5-HT; thus, the reversal of enhanced contractility to 5-HT may be merely a result of a reduction in the amount of neointima present. The present findings with 3 different contractile agonists, however, suggest that an additional clinical benefit of a FTase inhibitor may be to reduce the susceptibility of the artery to postangioplasty vessel spasm. In contrast, local paclitaxel administration has been shown to result in a major impairment of contractile function.22 Finally, the importance of farnesylation of Rho in mediating the migratory responses of SMCs to agonists such as thrombin is becoming more apparent.23,24 Thus, both SMC migration and proliferation should be prevented by an FTase inhibitor. Because FPTIII may act on Rho in addition to Ras, future studies will be needed to explore the relative importance of these 2 actions in neointima development.
Local drug delivery has a number of advantages over systemic drug delivery for the prevention of restenosis. FPTIII administration reduced adventitial thickening in response to injury in treated arteries. This has important implications, because adventitial hyperplasia is thought to play a major role in arterial remodeling,25 which also is a limiting factor in the success of clinical angioplasty.26 Because this aspect of the response to injury is often addressed by the use of intracoronary stents, which in themselves encourage SMC proliferation, the use of local drug delivery after injury may preclude the need for this. An additional benefit of local delivery is that sufficient concentrations of drug can be administered to the vessel wall while the risk of systemic side effects is limited.
Conclusions
The results of the present study show that a 15-minute application of an inhibitor of FTase by local delivery immediately after angioplasty has a profound effect on neointima formation assessed in pigs at a time when the process is complete. These findings could have a major impact on the success of clinical vascular reconstructive surgery and decrease the requirement for second angioplasty intervention or subsequent coronary bypass, providing a considerable improvement in the clinical efficacy of current balloon angioplasty techniques. Another major advantage is that short-term drug application would preclude the need for prolonged systemic or local (eg, coated stents) drug administration, which would limit the opportunity for adverse drug reactions to occur.
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Acknowledgments |
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Dr Work was supported by a Henry Dryerre Royal Society of Edinburgh Scholarship from the Carnegie Trust for the Universities of Scotland. Dr S. Pyne is a Wellcome Trust Senior Research Fellow. We are grateful to Hoechst-Marion-Roussel, Frankfurt, Germany, for financial assistance.
Received March 27, 2001; accepted June 26, 2001.
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