Novel E2F decoy oligodeoxynucleotides inhibit in vitro vascular smooth muscle cell proliferation and in vivo neointimal hyperplasia

Jd, Ahn; Morishita, Ryuichi; Kaneda, Yasufumi; Hs, Kim; Chang, Yeon Soo; Ku, Lee; Jy, Park; Hw, Lee; Yh, Kim; Ik, Lee

doi:10.1038/sj.gt.3301849

Cited by 41 publications

(33 citation statements)

References 32 publications

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“…26,27 Over the past decade, the transcription factor E2F has emerged as a key component of cellular proliferation, during which it controls the expression of genes required for cell cycle progression, 28,29 especially in high-glucose-stimulated VSMCs. 11,30 However, only a few investigators have examined the effects of pharmacological agents on E2F activity and VSMC proliferation. 31,32 Here, we show that cilostazol effectively reduces high-glucose-stimulated E2F activity, as well as proliferation of HVSMCs in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…11 Tissue collection was approved by the local Ethics Committee. HVSMCs were cultured in DMEM (Gibco BRL, Grand Island, NY) containing 20% fetal bovine serum (Gibco BRL).…”

Section: Cell Culturementioning

confidence: 99%

“…11 Cilostazol (100, 30, and 10 mg/d per kg) was administered daily by gavage, and balloon injury was performed on day 4. Rats were anesthetized with 50 mg/kg of sodium pentobarbital (Entobar; Hanlim Pharmaceutical, Yong-In, Korea).…”

Section: Rat Carotid Artery Balloon Injurymentioning

confidence: 99%

“…11 Briefly, the DNA probe for E2F was labeled with [␥-32 P]ATP and T4 polynucleotide kinase. After end-labeling, the probe was purified with a NAP-5 column.…”

Section: Electrophoretic Mobility Shift Assaymentioning

confidence: 99%

“…8 -10 We recently showed that high glucose activates the DNA-binding activity of E2F, and decoy oligodeoxynucleotides against E2F inhibit the proliferation of VSMCs. 11 These data suggest that downregulation of E2F could constitute a therapeutic target to prevent restenosis after angioplasty in patients with diabetes.…”

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confidence: 99%

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Cilostazol Inhibits Vascular Smooth Muscle Cell Growth by Downregulation of the Transcription Factor E2F

et al. 2005

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Abstract-Neointimal formation, the leading cause of restenosis, is caused by proliferation of vascular smooth muscle cells (VSMCs). Patients with diabetes mellitus have higher restenosis rates after coronary angioplasty than nondiabetic patients. Cilostazol, a selective type 3 phosphodiesterase inhibitor, is currently used to treat patients with diabetic vascular complications. Cilostazol is a potent antiplatelet agent that inhibits VSMC proliferation. In the present study, we examine whether the antiproliferative effect of cilostazol on VSMCs is mediated by inhibition of an important cell cycle transcription factor, E2F. Cilostazol inhibited the proliferation of human VSMCs in response to high glucose in vitro and virtually abolished neointimal formation in rats subjected to carotid artery injury in vivo. Moreover, the compound suppressed high-glucose-induced E2F-DNA binding activity, and the expression of E2F1, E2F2, cyclin A, and PCNA proteins. These data suggest that the beneficial effects of cilostazol on high-glucose-stimulated proliferation of VSMCs are mediated by the downregulation of E2F activity and expression of its downstream target genes, including E2F1, E2F2, cyclin A, and PCNA. The transcription factor, E2F, has been implicated in the periodic regulation of cellular genes required for transition through G1 and entry into the S phase, including dihydrofolate reductase, c-myc, DNA polymerase, cdc2, and proliferating cell nuclear antigen (PCNA). 5-7 E2F activity is regulated by interactions with RB family members. As cells progress toward S phase, RB family proteins are phosphorylated by G1 cyclin-complexes, resulting in the release of transcriptionally active E2F, which then leads to the activation of genes required for cell cycle progression. 8 -10 We recently showed that high glucose activates the DNA-binding activity of E2F, and decoy oligodeoxynucleotides against E2F inhibit the proliferation of VSMCs. 11 These data suggest that downregulation of E2F could constitute a therapeutic target to prevent restenosis after angioplasty in patients with diabetes.Cilostazol increases intracellular cAMP concentrations by selectively blocking phosphodiesterase type III. The clinical implications and pharmacokinetics with respect to the effects and safety of this drug have been well-established, especially in peripheral vascular disease. 12 Cilostazol is a potent antiplatelet agent currently used in clinical practice to treat patients with diabetic vascular complications. [13][14][15] Several lines of evidence indicate that cilostazol additionally inhibits the proliferation of VSMCs, reduces neointimal formation in balloon-injured rat carotid arteries, 16 -18 and inhibits restenosis after percutaneous transluminal coronary angioplasty. 19,20 One mechanism by which cilostazol may inhibit VSMC proliferation is via an increase in intracellular cAMP, because cAMP inhibits the proliferation of VSMCs by induction of p53-mediated and p21-mediated apoptosis. 21 However, Nadri et al demonstrated that increased cAMP...

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Section: Discussionmentioning

confidence: 99%

“…11 Tissue collection was approved by the local Ethics Committee. HVSMCs were cultured in DMEM (Gibco BRL, Grand Island, NY) containing 20% fetal bovine serum (Gibco BRL).…”

Section: Cell Culturementioning

confidence: 99%

Section: Rat Carotid Artery Balloon Injurymentioning

confidence: 99%

“…11 Briefly, the DNA probe for E2F was labeled with [␥-32 P]ATP and T4 polynucleotide kinase. After end-labeling, the probe was purified with a NAP-5 column.…”

Section: Electrophoretic Mobility Shift Assaymentioning

confidence: 99%

mentioning

confidence: 99%

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Cilostazol Inhibits Vascular Smooth Muscle Cell Growth by Downregulation of the Transcription Factor E2F

et al. 2005

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Synthesis and Characterization of Oligodeoxynucleotides Containing Naphthyridine:Imidazopyridopyrimidine Base Pairs at their Sticky Ends. Application as Thermally Stabilized Decoy Molecules

Hikishima¹,

Minakawa²,

Kuramoto³

et al. 2006

ChemBioChem

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We describe the synthesis and properties of oligodeoxynucleotides (ODNs) containing 1,8-naphthyridine C-nucleoside (Na-NO) and imidazo[5',4':4,5]pyrido[2,3-d]pyrimidine nucleoside (Im-ON) at the termini. The modified ODNs were more resistant (6 to 40 times) than natural DNA to snake venom phosphodiesterase (SVPD). Although incorporation of one pair each of Na-NO:Im-ON on the sticky ends of the duplex was insufficient for thermal stabilization (+2.5 degrees C per pair relative to the G:C pair), the duplex containing two consecutive Na-NO:Im-ON pairs at its sticky ends was markedly stabilized thermally. The stabilizing effect of the incorporation of additional Na-NO:Im-ON pairs is estimated to be +7.8 degrees C per pair. Application as thermally stabilized decoy molecules to NF-kappaB (p50) was also demonstrated. The DNA duplexes containing the Na-NO:Im-ON pairs (ODN I:ODN II and ODN III:ODN IV) acted as competitors to the natural NF-kappaB-binding duplex (ODN V: ODN VI), and the calculated IC50 values of ODN I:ODN II and ODN III:ODN IV were 20.1+/-13.3 and 10.9+/-4.8 nM, respectively, greater than that of ODN V:ODN VI.

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Increase in nuclease resistance and incorporation of NF‐κB decoy oligodeoxynucleotides by modification of the 3′‐terminus

Osako

Tomita

Nakagami

et al. 2007

The Journal of Gene Medicine

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Although R-ODN have a phosphodiester backbone, their physical conformation was designed to provide nuclease resistance without interfering with their binding activity. As expected, R-ODN showed more resistance to exonucleases and stability in 100% serum than non-modified decoy ODN (N-ODN). Importantly, the R-ODN construction did not interfere with its binding activity to NF-kappaB, similar to N-ODN. Transfection of R-ODN significantly inhibited the expression of MMP-9 induced by TNF-alpha in VSMC as assessed by real-time polymerase chain reaction (PCR), and R-ODN also inhibited the proliferation of VSMC induced by TNF-alpha (10 ng/ml), similar to phosphorothioate decoy ODN. Overall, the development of ribbon NF-kappaB decoy ODN could provide a useful tool for basic and clinical research.

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Novel E2F decoy oligodeoxynucleotides inhibit in vitro vascular smooth muscle cell proliferation and in vivo neointimal hyperplasia

Cited by 41 publications

References 32 publications

Cilostazol Inhibits Vascular Smooth Muscle Cell Growth by Downregulation of the Transcription Factor E2F

Cilostazol Inhibits Vascular Smooth Muscle Cell Growth by Downregulation of the Transcription Factor E2F

Synthesis and Characterization of Oligodeoxynucleotides Containing Naphthyridine:Imidazopyridopyrimidine Base Pairs at their Sticky Ends. Application as Thermally Stabilized Decoy Molecules

Increase in nuclease resistance and incorporation of NF‐κB decoy oligodeoxynucleotides by modification of the 3′‐terminus

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