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Ann Thorac Surg 2002;74:1132-1137
© 2002 The Society of Thoracic Surgeons

Original article: cardiovascular

Intraoperative transfection of vein grafts with the NF{kappa}B decoy in a canine aortocoronary bypass model: a strategy to attenuate intimal hyperplasia

Takuji Shintani, MDa, Yoshiki Sawa, MDa, Toshiki Takahashi, MDa, Goro Matsumiya, MDa, Nariaki Matsuura, MDb, Yuji Miyamoto, MDa, Hikaru Matsuda, MDa*

a Department of Surgery, Course of Interventional Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
b Department of Pathology, School of Allied Sciences, Faculty of Medicine, Osaka University, Osaka, Japan

Accepted for publication June 17, 2002.

* Address reprint requests to Dr Matsuda, Department of Surgery, Course of Interventional Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
e-mail: matsuda{at}surg1.med.osaka-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: The nuclear transcriptional factor NF{kappa}B is reported to play an important role in the expression of genes for neutrophil and macrophage chemotactic factors, adhesion molecules, and cell cycle–regulating proteins. In aortocoronary bypass surgery, the saphenous vein often develops vein graft disease. Here, we investigated whether transfection of a cis element decoy oligodeoxynucleotide of NF{kappa}B (NF{kappa}B decoy) into the vein graft wall suppresses neointimal hyperplasia and the differentiation of medial smooth muscle cells.

METHODS: We established a canine aortocoronary bypass grafting model that has a saphenous vein graft between the left anterior descending coronary artery and the descending aorta. Pressure-mediated transfection of a scrambled (SD group; n = 5) or NF{kappa}B decoy (ND group; n = 5) into the graft wall was performed intraoperatively. The grafts were gently harvested at 4 weeks postoperative, and the middle portion of the graft was examined histopathologically.

RESULTS: The average neointimal area of the ND group was significantly suppressed (SD group, 2.63 ± 1.00 mm2 vs ND group, 0.88 ± 0.66, p < 0.05), and the differentiation and proliferation of the medial smooth muscle cells in the ND group were also suppressed (proliferating cell nuclear antigen index: SD group, 56 ± 24 vs ND, 13 ± 4, p < 0.05).

CONCLUSIONS: These results demonstrated the efficacy of intraoperative transfection of the NF{kappa}B decoy into the vein graft wall for attenuation of neointima formation.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
The saphenous vein graft (SVG) is a very important graft in current coronary artery bypass grafting (CABG) procedures. However, the late patency rate is reported to be inferior to that of arterial grafts such as the internal thoracic artery, limiting its use and increasing the use of the arterial conduit in recent years [1–4]. The ability to prevent vein graft disease (VGD) would increase the use of vein grafts, which are more widely applicable.

VGD is thought to result from the stenosis of vein grafts by a marked neointimal hyperplasia that occurs when vein grafts are applied to arterial circulation. The histologic changes in vein grafts in arterial circulation were investigated by Cox and associates, who showed that fibrointimal hyperplasia with infiltration of macrophages and neutrophils occurs within 1 year, with atherosclerotic lesions becoming major features after 1 year [5]. It was further reported by Angelini and associates that three morphologic processes contribute to the medial and intimal thickening. The first is an initial phase of rapid smooth muscle cell proliferation in the media for the first week after grafting. The second is smooth muscle cell migration, hypertrophy, and synthesis of extracellular matrix between 1 and 4 weeks in both the media and the neointima. The last process is a late phase of slow smooth muscle cell proliferation in the neointima that occurs more than 4 weeks after grafting [6].

Recent studies have refined our understanding of the mechanisms of neointima formation. Intimal hyperplasia is caused by the differentiation, proliferation, and migration of medial smooth muscle cells as a result of the differences in tension and shear stress on the vein graft under arterial circulation. The surgical preparation may also cause intimal hyperplasia, because the loss of endothelium and functional damage to the vessel wall can cause activation of inflammatory cytokines, growth factors, and platelets [7–12].

NF{kappa}B is a nuclear transcriptional factor that seems to function as a switch for the primary response when a cell receives external stimulation, and it modulates the expression of genes for neutrophil and macrophage chemotactic factors, adhesion molecules, and proteins that regulate the cell cycle. In the mechanism of vein graft disease, rapid smooth muscle cell proliferation after neutrophil and macrophage migration occurs in the media for the first week, and extracellular matrix is synthesized in both the media and the neointima between 1 and 4 weeks after vein grafting. Therefore, we hypothesized that the suppression of NF{kappa}B activation in the media for at least 4 weeks postoperative might attenuate the excessive neointimal hyperplasia formation in the SVGs used in CABG. To investigate this possibility, we established an experimental CABG model that simulated actual CABG in the dog. We then used this model to investigate the efficacy of an NF{kappa}B decoy for attenuating neointimal hyperplasia by performing a modified intraoperative pressure-mediated transfection of the NF{kappa}B decoy into the vein graft wall.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
Sequence of oligodeoxynucleotides and preparation of the decoy
The sequences of the oligodeoxynucleotides used for this study were as follows. NF{kappa}B decoy: 5'-CCTTGAAGGGATTTCCCTCC-3', '-GGAACTTCCCTAAAGGGAGG-5', scrambled decoy: 5'-TTGCCGTACCTGACTTAGCC-3', 3'-AACGGCATGGACTGAATCGG-5'

The oligodeoxynucleotides were stored at -20°C until the operative day, after which they were stored at 4°C until the transfection. For the transfection, solutions of 40 µmol/L oligodeoxynucleotide in 0.9% saline were used at room temperature.

Modified pressure-mediated transfection method
A pressure-mediated transfection method [13] that has already been applied clinically in the US was used [14]. The scrambled or NF{kappa}B decoy solution (40 µmol/L) was introduced into the vein graft wall at less than 200 mm Hg pressure for 20 minutes at room temperature. Mann and associates developed a device for the transfection of vein segments that eliminated pressure-induced distension. We modified this device and introduced the oligodeoxynucleotides into the vessel wall. Briefly, vessel segments were secured to a cannula and the distal end of the vein was opened. The segments were also surrounded by a disposable syringe mounted proximally on the cannula, and the syringe was connected to a transducer. The decoy solution was then introduced under pressure through the lumen of the vein as well as into the syringe cavity. Thus, the vein was surrounded by pressurized oligodeoxynucleotide solution both lumenally and ablumenally.

Detailed data about the pressure-mediated transfection have been reported by Mann and associates [13]. In a preliminarily study, we also examined the transfection efficiencies under various transfection pressures and times. This experiment indicated that the transfection efficiency at less than 200 mm Hg pressure for 20 minutes was not much less than the transfection efficiency at less than 300 mm Hg pressure for 10 minutes (data not shown). In fact, at the beginning of this study, we performed the pressure-mediated transfection at less than 300 mm Hg pressure for 10 minutes, because those were the conditions chosen in a clinical trial for leg artery bypass grafting surgery [14], but the neointima formation of the vein grafts was very high in both the NF{kappa}B decoy and scrambled decoy transfection groups. This led us to consider that the conditions of 300 mm Hg pressure for 10 minutes were not optimized, at least for the transfection of decoy into the vein grafts used for coronary artery bypass grafting. Therefore, we tested other conditions and found that 200 mm Hg pressure for 20 minutes was optimal for transfection, and carried out the present study using these conditions.

The distribution of oligodeoxynucleotides (ODNs) by pressure-mediated transfection was evaluated histochemically with fluorescent isothiocyanate (FITC)-labeled ODNs (FITC-ODNs) (Fig 1 ). After evaluation of the distribution of the FITC-ODNs by pressure-mediated transfection, the same cross section was stained with hematoxylin eosin (HE). The transfection efficiency of the decoy was then calculated. The average transfection efficiency of the decoy was 77% ± 20%.



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  		Fig 1. Localization of fluorescent isothiocyanate (FITC)-labeled oligodeoxynucleotides (ODNs). Concentrated green FITC-labeled ODN signals are indicated in this fluorescence photomicrograph. ODNs are seen in the nuclei of the media and intima. Arrows indicate FITC-labeled ODNs in the nuclei of the media (x100 magnification). The numbers of FITC-positive and hematoxylin-positive nuclei were counted by using the public-domain image processing and analysis program (image, x 100 magnification). The average transfection efficiency of the decoy on the cross-section, defined as the ratio of the number of FITC-positive nuclei to the total number of nuclei based on hematoxylin staining, was 77% ± 20%.

 
The canine CABG model: surgical procedures
Mongrel dogs weighing 18 to 20 kg (NRB; Nihon Nosan, Kanagawa, Japan or HBD; Oriental Yeast Corporation, Osaka, Japan) fed a standard diet were used. After administration of ketamine (5 mg/kg body weight, IM), intratracheal intubation was performed. Under general anesthesia, maintained by inhalation of 1.5% sevoflurane, the SVG was harvested from the left hind leg of the dog. A longitudinal incision was made on the outer part of the leg to expose approximately 10 cm of the saphenous vein. The vein was dissected free of surrounding tissue using a "no touch technique" [15], and all the side branches were secured with a 4-0 silk ligature. The vein was then removed from the dog and irrigated with heparinized 0.9% saline solution without distension [16]. All veins were then stored in the same solution at room temperature for about 60 minutes. A left fourth intercostal thoracotomy was performed, and pressure-mediated transfection of the scrambled decoy (SD group; n = 5) or the NF{kappa}B decoy (ND group; n = 5) into the vein graft wall was performed. After intravenous injection of heparin (100 U/kg body weight), the saphenous vein graft was interposed between the descending aorta and the left anterior descending coronary artery (LAD) using the off-pump CABG technique; that is, the end-to-side anastomosis between the vein graft and the left anterior descending coronary artery was performed on the beating heart with 7-0 Prolene suture (Ethicon, Inc, Somerville, NJ) using an "Octopus" (Medtronic Inc, Minneapolis, MN) stabilizer, and the other end of the vein graft was sutured to the descending aorta with 6-0 Prolene in an end-to-side fashion, and then the proximal LAD was ligated with 4-0 Prolene.

At 4 weeks postoperative, the dogs were sacrificed, and the grafts were gently harvested. We then examined the degree of neointimal formation and differentiation and proliferation of the medial smooth muscle cells in the ND and SD groups.

The procedures were in accordance with the guidelines approved by the Institutional Animal Care and Use Committee, Osaka University Graduate School of Medicine. All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (National Institutes of Health publication No.86 to 23, revised 1985).

Animal sacrifice and tissue preparation
An antibiotic (CEZ; Fujisawa Pharmaceuticals, Osaka, Japan) was administered to the dogs by the 3rd postoperative day. At 4 weeks postoperative, the dogs were sacrificed and the grafts were gently harvested, dissected, and briefly rinsed in 0.9% saline solution. The middle portion of the graft was then divided into three parts, which were approximately 5 mm thick. The pieces were frozen in OCT compound (Miles Scientific, Tokyo, Japan) in a cryomold in liquid nitrogen. The pieces were cut into cross sections approximately 5 µm thick and stained with hematoxylin and eosin (H&E) as a routine stain or Masson-Trichrome stain as an extracellular matrix stain, and by the immunohistochemical technique described below.

Immunohistochemical studies
The frozen sections, approximately 5 µm thick, were cut from a fresh-frozen block of tissue and immunostained for {alpha}-actin and proliferating cell nuclear antigen (PCNA). Monoclonal antibodies against smooth muscle–specific {alpha}-actin (Histofine; Nichirei, Tokyo, Japan) and PCNA (PC-10; Dako, Tokyo, Japan) were used as specific markers for smooth muscle cells, and differentiating and proliferating cells, respectively.

Immunohistochemical staining was performed using the immunoperoxidase avidin-biotin complex system with nickel chloride color modification [17].

Measurements of neointimal and medial areas
The cross sections cut from fresh-frozen blocks of each graft were stained with H&E, and the areas of the neointima and media were measured on these stained sections using the computerized image analysis program, "image."

Quantification of cell proliferation in the media
The cross sections of fresh-frozen blocks of each graft were stained with a monoclonal antibody against PCNA, and measured using NIH image. The numbers of PCNA-positive and hematoxylin-positive nuclei in the media were counted using NIH image at x200. The frequency of cell proliferation was expressed as the PCNA index, which was defined as the ratio of the number of PCNA-positive nuclei to the total number of nuclei in the media.

Statistical analysis
All values are expressed as the means ± SD. Student’s nonpaired t test was used for comparisons between two groups. Statistical significance was set at p less than 0.05.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
Neointimal formation and medial thickening were assessed on the cross sections cut from the middle portion of the H&E-stained grafts. Neointimal hyperplasia of the ND group was significantly suppressed in comparison with the SD group (Fig 2 ).



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  		Fig 2. Cross-sections of the middle portion of vein grafts.Arrows indicate the internal elastic lamina. The medial and intimal areas were calculated by using the computerized image analysis program, image. In comparison with that of the scrambled decoy group (a), neointimal hyperplasia of the NF{kappa}B decoy group (b) was significantly suppressed. (Hematoxylin & eosin staining, x40 magnification.) (I= intima;M= media.)

 
The average areas of the neointima and the media measured on the cross sections at 4 weeks postoperative are shown in Table 1. The ratio of the neointimal area to the medial area of the ND group was 0.62 ± 0.43, which was significantly lower than that of the SD group, 1.45 ± 0.45 (p < 0.05).


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  		Table 1. The Average Areas of the Neointima and the Media

 
Proliferation of the medial smooth muscle cells was evaluated immunohistochemically using monoclonal antibodies against smooth muscle–specific{alpha}-actin. The cross sections stained for {alpha}-actin showed that transfection of the NF{kappa}B decoy tended to suppress the medial smooth muscle cell proliferation (Fig 3 ).



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  		Fig 3. {alpha}-actin staining.Arrows indicate the internal elastic lamina. {alpha}-actin was stained brown immunohistochemically by using the immunoperoxidase avidin-biotin complex system with nickel chloride color modification. Transfection of NF{kappa}B decoy tended to suppress the proliferation of the smooth muscle cells in the media. (a) Scrambled decoy group. (b) NF{kappa}B decoy group. (x200 magnification.) (I = intima;M = media.)

 
The extent of differentiation and proliferation of the medial smooth muscle cells was assessed on the cross sections at 4 weeks postoperative using a monoclonal antibody against proliferating cell nuclear antigen (PCNA). The PCNA index of the ND group, 13 ± 4% (p < 0.05 vs SD group), was lower than that of the SD group, 56% ± 24%.

Masson-Trichrome staining showed a suppression of the excessive extracellular matrix synthesis in the neointima of the ND group (Fig 4 ).



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  		Fig 4. Extracellular matrix staining. Arrows indicate the internal elastic lamina. In Masson-trichrome staining, the extracellular matrix is stained blue. (a) Scrambled decoy group. In the (b) NF{kappa}B decoy group, suppression of superfluous synthesis of the extracellular matrix in the neointima was seen. (x100 magnification.) (I = intima;M= media.)

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
This study is the first to demonstrate in a large animal model the efficacy of the NF{kappa}B decoy for attenuating neointimal hyperplasia. This was previously investigated in vivo and in an alternative noncoronary bypass model. We showed that neointima formation of the ND group was significantly suppressed in comparison with that of the SD group. Therefore, the transfection of the NF{kappa}B decoy seemed to be effective for attenuating neointima formation.

Because the transfection efficiency using the pressure-mediated transfection procedure was not 100%, it is reasonable to assume that there were nuclei present in the grafts of the ND group that were not subject to the suppression of the NF{kappa}B activation. Therefore, neointima formation appeared in the ND group to some degree. Smooth muscle cell proliferation in the neointima was also seen in the ND group, in spite of the suppression of the differentiation and proliferation of the medial smooth muscle cells. Our results are consistent with the following scenario: within 4 weeks postoperative, due to a lack of endothelial cells, the platelets were activated at the exposed subendothelial tissues and the release of platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) occurred. These factors induced the differentiation and proliferation of the medial smooth muscle cells, which led to the formation of the neointima. In fact, a lack of endothelial cells and activation of platelets are closely associated with neointima formation [18]. Furthermore, it has been reported that neointimal hyperplasia is suppressed by introduction of the eNOS gene [19], or by anti-PDGF [20] or anti-bFGF antibodies [21].

We thought that the suppression of NF{kappa}B activation might have the advantage of inhibiting neutrophil adherence and macrophage infiltration over suppressing only the cell cycle. It has been reported that NF{kappa}B modulates the expression not only of genes that regulate the cell cycle, but also of the genes for neutrophil chemotactic factor (IL-8) [22], macrophage chemoattractant factors (MCP-1) [23], and adhesion molecules [24]. Furthermore, recent studies have suggested that the infiltration of neutrophils and macrophages into the neointima is closely associated with a slow smooth muscle cell proliferation and gradual extracellular matrix synthesis in the neointima that occur later than 4 weeks after grafting [5–12]. Therefore, we used the NF{kappa}B decoy for attenuating neointimal hyperplasia instead of the E2F decoy, which has already been proven to be effective in human trials. We thought that neutrophil and macrophage infiltration could easily occur within 4 weeks postoperative due to a loss of endothelial cells, and that the suppression of NF{kappa}B activation within 4 weeks postoperative might effectively decrease the slow smooth muscle proliferation and gradual extracellular matrix synthesis even more than 4 weeks after grafting.

It will still be necessary to examine the long-term results of neointimal hyperplasia histopathologically to evaluate the efficacy of NF{kappa}B decoy transfection for the prevention of VGD. However, for this study, we thought that 4 weeks of observation would be long enough to detect differences in neointima hyperplasia, because it has been reported that rapid smooth muscle cell proliferation in the media and rapid smooth muscle cell migration and extracellular matrix synthesis in both the media and the neointima, with infiltration of macrophages and neutrophils, occur within 4 weeks [8]. Furthermore, it has been reported that vascular endothelial cells are completely regenerated within 4 weeks postoperative [25]. Endothelial cells inhibit the adhesion and migration of neutrophils and the activation of platelets. Therefore, we hypothesized that the suppression of neointimal hyperplasia and medial smooth muscle cell proliferation with infiltration of neutrophils and macrophages within 4 weeks after grafting might be an efficient strategy for preventing VGD.

Finally, we thought that physical injury to the vein graft might occur from the applied pressure and have a pathologic effect. Cross sections of the vein grafts that had received the applied pressure showed higher smooth muscle cell proliferation and extracellular matrix synthesis than sections from vein grafts that had not undergone pressure-mediated transfection. However, neointimal formation in the vein graft with pressure-mediated transfection of the NF{kappa}B decoy was significantly suppressed in comparison with that of the vein graft with pressure-mediated transfection of the scrambled decoy. Therefore, we concluded that transfection of the NF{kappa}B decoy was an efficient strategy for attenuating intimal hyperplasia, but that pressure-mediated transfection might not be a desirable transfection method.

Further study is required to improve the efficacy of NF{kappa}B decoy transfection. It will be necessary to develop a new transfection method that does not damage the graft tissue but can introduce oligodeoxynucleotides into the vessel wall with high efficiency.

Conclusions
This study demonstrated the efficacy of the NF{kappa}B decoy in attenuating neointima formation and the differentiation and proliferation of the medial smooth muscle cells for 4 weeks, and suggests its possible clinical application to attenuate the neointimal hyperplasia of vein grafts that occurs after CABG.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
We thank Shigeru Matsumi and Akiko Nishimura for their excellent technical assistance and Dr Naomasa Kawaguchi for his useful advice on the histopathologic analysis.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

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