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Am J Physiol Heart Circ Physiol 288: H2203-H2209, 2005. First published January 6, 2005; doi:10.1152/ajpheart.00555.2004
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Antisense oligodeoxyribonucleotide as to the growth factor midkine suppresses neointima formation induced by balloon injury

Kenji Hayashi ,1,* Hiroshi Banno,1,2,* Kenji Kadomatsu,1 Yoshifumi Takei,1 Kimihiro Komori,2 and Takashi Muramatsu1

Departments of 1Biochemistry and 2Vascular Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan

Submitted 8 June 2004 ; accepted in final form 30 December 2004


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Restenosis is the major clinical problem of angioplasty. We have previously shown that neointima formation is strikingly suppressed in midkine (MK)-deficient mice. Neointima formation is restored if MK protein is administrated to the deficient mice. MK is a heparin-binding growth factor and implicated in the migration of inflammatory cells and vascular smooth muscle cells. Consistently, the suppression of neointima formation in the deficient mice is accompanied by suppression of recruitment of inflammatory cells into the vascular wall. Here, we evaluated the potential of MK antisense oligodeoxyribonucleotide (ODN) for the prevention of restenosis. We cloned the cDNA of rabbit MK, which showed a strongly conserved sequence in mammals. The balloon injury induced MK expression, with the maximum level occurring 7–14 days after angioplasty, in the rabbit carotid artery. Two antisense ODNs suppressed the production of MK in a rabbit kidney cell line, RK13 cells, one of which was then transfected into the arterial wall by means of lipofection immediately after balloon treatment. The antisense ODN suppressed MK induction in vivo and consequently suppressed neointima formation to 60% of the control level. These results suggest that MK is a candidate molecular target for the therapy for vascular restenosis.

molecular target; phosphorothioate; vascular restenosis

SINCE ANDRES GRÜNTZIG performed the first percutaneous transluminal coronary angioplasty in 1977, it has become the major means of coronary revascularization, accounting for more than 1,500,000 procedures worldwide every year (1). However, 30–60% of patients face the problem of restenosis within 6 mo (3), which lowers the procedure's efficacy. Although the advent of coronary stent has reduced the incidence of restenosis, the in-stent stenosis rate is still 15–20% for ideal coronary lesions and may increase to over 30–60% for patients with complex lesions (e.g., small vessel, diffuse atheromasia and bifurcation lesions) (8).

The pathogenesis of restenosis is ascribed to a cascade of molecular and cellular events in the vascular wall. The complex processes can be divided into two major categories, i.e., arterial negative remodeling and neointima formation (34). Replacement of hyaluronic acid with collagen in the extracellular matrix and adventitial thickening are thought to be involved in negative remodeling after angioplasty (37, 41). On the other hand, both angioplasty and stenting cause injury to the vascular wall, with platelet accumulation and activation and smooth muscle cell activation being initiated. These consequently induce smooth muscle cell migration from the media to the intima and proliferation there, leading to neointima formation (39).

Midkine (MK) is a heparin-binding growth factor that was originally discovered as the product of a retinoic acid-responsive gene (14, 45). MK has 50% sequence identity with pleiotrophin/heparin-binding growth-associated molecule (7, 19, 30, 36). These two form a family distinct from other heparin-binding growth factors. We previously demonstrated that MK-deficient mice exhibit a striking reduction of neointima formation in a restenosis model, which is reversed on systemic MK administration (12). In MK-deficient mice, neutrophils and monocytes/macrophages are recruited less to the arterial wall, which is consistent with MK exhibiting a chemotactic activity toward neutrophils, macrophages, and vascular smooth muscle cells (12, 43). MK expression is transiently increased, with the maximum level being reached at day 7, in a rat balloon injury model, where the neointima formation is completed around day 14. MK protein becomes detectable in smooth muscle cells in the neointima. Therefore, MK is essential for neointima formation and is restrictively induced in the vascular wall during this process. These features match the requirements for a molecular target for therapy for vascular restenosis and thus prompted us to evaluate the MK antisense oligodeoxyribonucleotide (ODN) strategy as a therapy for vascular restenosis in the present study.


   MATERIALS AND METHODS
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 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
cDNA cloning of rabbit MK. The degenerate primers used were forward 1, 5'-ATGCAGCACCGARGYCCTCYTCTCCTC-3'; forward 2, 5'-CCCTBGAACTGGAAGAA-3'; and reverse 1, 5'-TTBCCTTTCTTGSCTTTGG-3' (R: A or G; Y: C or T; B: C, G, or T; S: G or C). Forward 1 contains the initiation codon, corresponding to 1–27 nt of human MK cDNA, forward 2 is in the middle, corresponding to 217–233 nt, and reverse 3 is near the stop codon, corresponding to 401–419 nt. The 5' and 3' rapid amplification of cDNA end kits were obtained from Takara Bio. The strategy for cDNA cloning of rabbit MK is described in RESULTS. The GenBank accession number of the rabbit MK cDNA sequence is AY553907.

Design of rabbit MK antisense ODNs. The design of antisense ODNs was performed as described previously (44). The sequences synthesized were as follows (see also Fig. 1A) : AS1, 5-'AAGGGTGAGGAGGAGGA-3'; AS2, 5'-GGCGAGAAGGGTGAGGAG-3'; AS3, 5'-CTTGTCTTTCTTTTTG-3'; AS4, 5'-CTCGGTGCTGCATCTCGC-3'; and AS5, 5'-GCCTCGGTGCTGCATCT-3'. The sense (S) and scramble (Scr) sequences for AS3 were as follows: S, 5'-CAAAAAGAAAGACAAG-3'; and Scr, 5'-TTCGTTCTTTTTGTCT-3'. All ODNs were synthesized with a phosphorothioate backbone. They were synthesized with an automated solid-phase nucleotide synthesizer (Expdite8900 Nucleic Acid Synthsis System, Applied Biosystems) and subsequently purified using a Wakopak Handy ODS column (Waters).



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  		Fig. 1. Sequence of rabbit midkine (MK) cDNA. A: full-length cDNA sequence and deduced amino acid sequence. The target sequences for antisense oligodeoxyribonucleotides (ODNs) are indicated. The polyadenylation signal is underlined. B: aligned mammalian MK amino acid sequences. Conserved residues in at least 3 species are boxed. All cysteine redidues are conserved and indicated by solid circles.

 
Cell culture and in vitro transfection. The rabbit kidney cell line RK13 was obtained from the American Type Culture Collection and maintained with 10% FBS in DMEM. Transfection of ODNs was performed with LipofectAmine Plus (Invitrogen) as described previously (44). After transfection (incubation in serum-free medium for 3 h), the cells were incubated with 10% FBS in DMEM for 4 h to recover their viability. The medium was then replaced with DMEM containing insulin (10 µg/ml), transferrin (5.5 µg/ml), sodium serenite (6.7 ng/ml), and heparin (20 µg/ml). After 16 h, the medium was collected for Western blot analysis.

Rabbit arterial restenosis model. Rabbits (Japanese White, 2.5–3 kg) were anesthetized with ketamine (35 mg/kg) and xylazine (10 mg/kg). Neither mechanical ventilation nor supplemental fluid administration was required. Rabbits were systemically heparinized (200 U/kg). A catheter for angioplasty (Open Seil: 2 x 15 mm) was inserted into the common carotid artery and then pushed and pulled 10 times at 8 atm. During the angioplasty, 10 µl of an ODN (1 mM) and 20 µl of Plus reagent (Invitrogen) were mixed with PBS (total: 50 µl), incubated for 15 min at room temperature, and then mixed with a mixture of LipofectAamine reagent (8 µl) and PBS (42 µl). After incubation for 15 min at room temperature, this transfection mixture was mixed with 400 µl of PBS. Transfection of an ODN to the injured area was performed by injecting ~100 µl of the transfection mixture (20 µM/site), followed by incubation for 1 h before the blood flow was restarted. The animal experiments in the present study were performed in compliance with the guidelines of the Institute for Laboratory Animal Research, Nagoya University Graduate School of Medicine.

Arteries (2 cm) removed on the indicated days were subjected to Western blot and morphometric analyses. For Western blot analysis, arteries were lysed in 1 ml of 10 mM Tris·HCl (pH 7.4) with 150 mM NaCl, 1% Triton X-100, and 1 mM phenylmethylsulfonyl fluoride. The supernatant of the lysate obtained on centrifugation (10,000 g, 30 min at 4°C) was mixed with heparin-Sepharose CL-4B (50% slurry, Amersham Bioscience) for 1 h at 4°C. Because the heparin-bound fraction contained MK, the heparin-Sepharose beads were washed three times with lysis buffer followed by three times wash with lysis buffer containing 0.5 M NaCl. The heparin-bound fraction was then subjected to Western blot analysis. For morphometric analysis, the arteries were fixed in 4% paraformaldehyde and then stained with hematoxylin and eosin staining. The areas of the intima and media were measured using imaging software (ImageJ). The area of the scraped region (~1 cm in length after both 5 mm-ends were removed) was examined at an interval of 1 mm. Statistical analysis was carried out by means of the Mann-Whitney U-test. To estimate the persistency of ODNs in the artery wall after transfection, arteries were removed after transfection of FITC-conjugated AS3 and snap frozen in liquid nitrogen. Four-micrometer-thick sections were cut with a cryostat and stained with propidium iodide to localize nuclei. Fluorescence was observed under a confocal microscope system (MRC 1024, Bio-Rad).


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
cDNA cloning of rabbit MK. To evaluate the MK antisense ODN as a therapeutic agent of arterial restenosis, we decided to employ a rabbit balloon injury model and, first, cloned rabbit MK cDNA. We designed degenerate primers based on mouse, rat, human, bovine, and Xenopus MK cDNA sequences and obtained a partial sequence of rabbit MK cDNA (data not shown). Subsequently, full-length rabbit MK cDNA was obtained by means of 5' and 3' rapid amplification of the cDNA end method. Rabbit MK cDNA encoded a putative secretory protein with 142 aa (Fig. 1A), which had a 94% and 86% identity with human and mouse MK, respectively (Fig. 1B). All 10 cysteine residues were conserved. These results indicate that MK is evolutionally well conserved.

Effect of rabbit MK antisense ODNs on MK expression of cultured cells. Five rabbit MK antisense ODNs were designed to target loop regions of the mRNA, which were predicted from the secondary structure deduced by use of the algorithm of Zuker and Stiegler (Fig. 1A) (48). We synthesized them with a phosphorothioate backbone because it is much more resistant to nucleases than a natural phophodiester backbone and thus is commonly used for ODN-utilizing therapies (26).

To evaluate the efficacy of each ODN on MK expression, possible candidate cells could be primarily cultured vascular wall cells. However, the transfection efficiency of ODN into the primarily cultured cells is generally low, and the vascular wall cells express a low amount of MK in the physiological state. RK13 cells are derived from the rabbit kidney and abundantly express MK. Therefore, we decided to use RK13 cells in this study. As predicted from the strong conservation of MK, rabbit MK was well recognized by anti-human MK antibody on Western blot analysis (Fig. 2A, "C"). Two ODNs, AS3 and AS4, strongly suppressed MK production of RK13 cells, a rabbit kidney cell line, to 16% and 18% of the untreated level, respectively (Fig. 2B). These ODNs do not contain a CpG motif (GACGTT), which is known to induce an immunological reaction if administered to animals (17, 22). These do not contain a GGGG sequence (G quartet) either, which has been reported to be responsible for the nonspecific inhibitory effects of phosphorothioate-modified ODNs on vascular smooth muscle cells (6, 47). Therefore, it is conceivable that AS3 and AS4 are useful for further in vivo studies.



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  		Fig. 2. Effects of antisense ODNs on MK production of rabbit kidney cell line RK13. A: culture medium containing heparin at 20 µg/ml was collected 23 h after ODN transfection and then subjected to Western blot analysis for MK protein. Experiments were performed independently 3 times and gave similar results, with a reperesentative result shown here. B: densitometirc analysis indicated that AS3 and AS4 suppressed MK protein production to 16% and 18% of the untreated control (C) level, respectively.

 
MK expression in the rabbit carotid artery after balloon injury. Although MK expression was detected before and 1 day after balloon injury on Western blot analysis in a longer exposure (data not shown), MK protein expression was then dramatically enhanced, with the maximum level being reached between 7 and 14 days after balloon injury (Fig. 3). MK induction became conspicuous at later stages rather than the initial stages, taking into account that neointima formation is completed within 14 days after balloon treatment (data not shown) (35). This time course was essentially the same as that of MK in a rat model (12).



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  		Fig. 3. Time course of MK expression in the rabbit balloon injury model. A and B: the MK protein band was enhanced at 3 days after balloon injury, with the maximum level being reached around 7–14 days. Experiments were performed independently 3 times and gave the similar results, with a reperesentative result shown here. In B, the relative densitometric densities of the MK bands in A standardized as to {beta}-actin bands are shown.

 
Effects of MK antisense ODN on intimal thickening. We next examined the effect of an MK antisense ODN, AS3, on MK expression in the carotid artery after balloon injury. AS3 was transfected into the arterial wall by means of lipofection by incubation for 1 h immediately after balloon treatment. Figure 4A shows that this transfection achieved a good infiltration of transfected ODN through the arterial wall 6 h after transfection. However, ODN persisted in the artery wall no longer than 24 h (Fig. 4A). AS3 suppressed MK expression fairly well (~28% of the sense ODN-treated level), as estimated 4 days after balloon treatment, suggesting that this reagent could be a potent MK inhibitor applicable to therapy for arterial restenosis (Fig. 4, B and C). The effect of AS3 lasted at least for 7 days after transfection (Fig. 4D).



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  		Fig. 4. In vivo transfection of a rabbit MK antisense ODN. FITC-conjugated AS3 was transfected into the common carotid artery. A, top: localization of the ODN at 6 h after transfection (left). The nuclei were stained with propidium iodide (middle). A merge view of the ODN and nuclei stain is also presented (right). The elastic lamina of the vascular wall is well known to be autofluorescent. However, by merging the green signals with those of propidium iodide, we were able to detect that the transfected FITC-conjugated AS3 persisted in the wall at least 6 h after transfection. A, top middle and bottom middle: negative controls of no transfection and lipofection alone, respectively. A, bottom: localization of ODN 24 h after transfection. Bar = 50 µm. In B and C, the artery was transfected with AS3 (AS) or sense control (S), removed 4 days after transfection, and then subjected to Western blot analysis for MK expression. Experiments were performed independently 3 times and gave the similar results, with a reperesentative result shown here. The relative densitometric densities of MK bands in B standardized as to {beta}-actin bands are also shown (C). In D, MK expression was monitored 4, 7, and 14 days after transfection of ODN into the balloon-injured artery. Scramble (Scr), lipofection alone (Lip), and no transfection (NT) controls were included.

 
We used AS3 for the prevention of intimal thickening. To eliminate the influence of individual differences, we treated the two carotid arteries of the same individual rabbit with antisense and sense ODNs: the antisense ODN was administered to the left carotid artery and the sense one to the right, or vice versa. AS3 significantly suppressed intimal thickening compared with the sense control ODN (Fig. 5, A and B). AS3 caused an ~40% reduction.



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  		Fig. 5. Effects of a rabbit MK antisense ODN on intimal thickening induced by balloon injury. Arteries were removed 14 days after balloon angioplasty with MK antisense or sense ODN. They were then stained with hematoxylin and eosin (A). The ratio of intima and media (B) was calculated by means of an image analyzer as described in MATERIALS AND METHODS. The number of animals used for the experiment was 6; in 3 animals, the antisense ODN (AS3) was administered to the left carotid artery and the corresponding sense ODN to the right carotid artery, whereas in the other 3 animals the sense ODN was administered to the left and antisense one to the right. *P < 0.05 (by Mann-Whitney U-test). Bar = 50 µm.

 

   DISCUSSION
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 ABSTRACT
 MATERIALS AND METHODS
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To prevent restenosis, many procedures and devices have been developed. Among them, brachytherapy and drug eluting stents appear to be encouraging and promising procedures (4, 8, 34). Brachytherapy involves {beta}- or {gamma}-irradiation therapy for the prevention or treatment of restenosis. Brachytherapy suppresses cell proliferation, induces apoptosis, and inhibits cell migration, and thus reduces neointimal accumulation. However, this method also has significant adverse effects, including late thrombosis that can lead to late myocardial infarction. Drug-eluting stents involve the combination of a polymer for controlled drug release and a drug for suppression of neointima formation. Sirolimus is a natural macrocyclic lactone with potent immunosuppressive and antimitotic actions. Studies on sirolimus-eluting stent were started very recently and have so far demonstrated satisfactory effects on restenosis without adverse effects (16, 28). Stents eluting paclitaxel, a potent antiproliferative used for cancer treatment, also appear to be useful (4). Nevertheless, as brachytherapy and drugs used for drug-eluting stents, such as sirolimus and paclitaxel, have multiple actions on not only vascular smooth muscle cells but also endothelial cells and others, this nonspecificity should be a cause for concern. Indeed, a major concern of both brachytherapy and drug-eluting stents is the failure of complete vessel healing, which may lead to a lack of reendothelialization and late thrombosis (4). Therefore, molecular target-oriented therapy is an intriguing strategy if specificity for a disease is sought. One such molecular target may be a molecule that is specifically induced during neointima formation. As previously shown, MK-deficient mice exhibit decreased neointima formation, and exogenously administered MK restores it (12). We demonstrated here that MK is induced by balloon injury in the carotid artery and that MK antisense ODN suppresses its induction and consequently neointima formation. Thus these data collectively suggest that MK is a candidate molecular target for therapy for restenosis.

Recent studies have emphasized the involvement of inflammation and the proliferation of vascular smooth muscle cells in atherosclerosis and restenosis (21, 40). Accordingly, many molecular target-oriented therapies have been proposed: the targets include monocyte chemotactic protein-1 (27), activator protein-1 (18), E2F (24, 25), c-myc (20), and c-myb (10). Among them, E2F decoy ODNs are expected to suppress the proliferation of vascular smooth muscle cells and have so far shown encouraging results in clinical trials for human bypass vein grafts (24, 25). On the other hand, the induction of MK expression is associated with expression of chemokines, such as macrophage inflammatory protein-2 and monocyte chemotactic protein-1, in an ischemic renal injury model (38). In MK-deficient mice, expression of these molecules is suppressed, and, consequently, tubulointerstitial damage is strikingly suppressed (38). Consistently, neutrophils and monocytes/macrophages are recruited less to the arterial wall and the kidney in an arterial restenosis model and ischemic renal injury model, respectively, in MK-deficient mice (12, 38). Furthermore, MK exhibits a chemotactic activity toward neutrophils, macrophages, and vascular smooth muscle cells (12, 43). Therefore, MK could be a novel molecular target aiming at suppression of inflammation.

ODNs did not persist in the vessel wall until 24 h after transfection (Fig. 4A), when MK expression was still low (Fig. 3), whereas the suppressive effect on MK expression persisted until day 7 (Fig. 4D). Therefore, the discrepancy between the ODN persistency and its effect on MK expression should be carefully discussed. We recently encountered similar data in cisplatin-induced nephropathy (15). In this case, although MK expression was suppressed after cisplatin administration, MK-deficient mice exhibited less damage in the kidney and better survival than wild-type mice. Suppression of MK expression with MK antisense ODNs in wild-type mice also ameliorated the cisplatin-induced renal damage. The main cause of renal damage in this model was inflammation involving infiltration of neutrophils and macrophages. The present data could be explained by the same molecular mechanisms as in the cisplatin-induced renal damage. Thus we speculate that the existence of MK protein at the early phase in the milieu of balloon-damaged tissue is needed for the secondary effect of balloon injury, i.e., inflammation. Molecular circuits involving MK participate in early phase to induce inflammation. Such molecular circuits may initiate chain reactions, which make the inflammation worse and consequently induce the neointima formation. These chain reactions may also enhance MK, as shown in Fig. 3.

With regard to the action mechanisms of MK, protein tyrosine phosphatase-{zeta} (a receptor-type protein tyrosine phosphatase with chondroitin sulfate chain) and chondroitin sulfate are involved in MK-mediated cell migration (11, 23, 33). Another intriguing feature of MK is that it synergistically functions with platelet-derived growth factor (PDGF) in cell migration (33). PDGF is implicated in neointima formation and atherosclerosis (31). An antibody against PDGF or PDGF receptor kinase inhibitor suppresses neointima formation (2, 9). Antisense ODNs against PDGF receptor-{beta} effectively suppresses intimal thickening (32). On the other hand, we recently identified low-density lipoprotein receptor-related protein as a receptor for MK (29, 42). PDGF receptor-{beta} is negatively regulated by low-density lipoprotein receptor-related protein (5). Taken together, these data suggest that cross-talk between MK and PDGF play a pivotal role in neointima formation.

It is of note that MK expression is very low in adult tissues, although the expression is strongly induced in pathological states such as carcinomas and inflammation (13, 30, 38, 46). We examined the adverse effects of systemically administered mouse MK antisense ODNs on intravenous injection at a dose of 1 mg/kg and found no abnormalities in terms of gross morphology, behavior, or serum biochemical data (unpublished data). This feature is advantageous for making MK a molecular target for therapy because of the barely predictable adverse effects.

The effects of MK antisense ODNs were not strong enough to completely suppress neointima formation (40% reduction). One of the reasons may be that MK induction on the arterial wall is relatively slow (the maximum level being reached around 7–14 days after balloon treatment), whereas ODN transfection was performed immediately after balloon treatment. These phenomena are consistent with PDGF receptor-{beta} expression (peak 7 days after injury) and its knockdown by antisense ODNs (40% reduction of intimal thickening) in a rat carotid injury model (32). In contrast, c-myb is induced 18 h after injury, and an antisense ODN strikingly suppresses neointima formation (80% reduction) (10). Therefore, it is expected that the controlled release of MK antisense ODNs improves the effect. Stents eluting such an ODN would be an attractive device for solving this problem, but this remains to be examined.


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 ABSTRACT
 MATERIALS AND METHODS
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REFERENCES
 
This work was supported by grants from the Ministry of Education, Culture, Sport, Science and Technology of Japan and the Ministry of Health and Welfare of Japan.


   ACKNOWLEDGMENTS
 
We thank Shinya Ikematsu (Meiji Dailies) and Sadatoshi Sakuma (Cell Signals) for the MK antibody.


   FOOTNOTES
 

Address for reprint requests and other correspondence: K. Kadomatsu or T. Muramatsu, Dept. of Biochemistry, Nagoya Univ. School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan (E-mail: kkadoma{at}med.nagoya-u.ac.jp or tmurama{at}med.nagoya-u.ac.jp)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

* K. Hayashi and H. Banno contributed equally to this work. Back


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