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Locally applied antisense oligonucleotide to proliferating cell nuclear antigen inhibits intimal thickening in
G J Fulton1, M G Davies, L Barber
1Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
Abstract:
This study examines the effect of antisense oligonucleotide to proliferating cell nuclear antigen (PCNA) on the formation of vein graft intimal hyperplasia in vivo, using localized administration. Twenty-four New Zealand white rabbits had a right carotid interposition bypass graft using the external jugular vein and were sacrificed on the 28th postoperative day. To determine the effect of PCNA on the development of intimal hyperplasia, 6 animals had their grafts coated with a pluronic gel containing 18 base antisense oligonucleotide to PCNA (1 mg/ml), 6 received a pluronic gel containing an 18 base nonsense oligonucleotide (1 mg/ml), and 12 animals were controls (6 with and 6 without pluronic gel). These grafts were harvested for morphology and videomorphometry. There was no change in the intimal thickness between the control and gel-treated groups. (70 +/- 4 microm versus 72 +/- 4 microm; mean +/- s.e.m.; p = ns). The presence of nonsense oligonucleotide had no further effect. Antisense PCNA produced a 26% decrease in intimal thickness to 50 +/- 4 microm in the treated vein grafts (p < 0.03) without a change in medial thickness. This study shows that a local single application of antisense oligonucleotide to PCNA will reduce the intimal hyperplasia in experimental vein grafts over 28 days.
Insights
Local application of antisense oligonucleotide targeting proliferating cell nuclear antigen (PCNA) significantly reduced vein graft intimal hyperplasia in a rabbit model. This targeted approach offers a promising strategy for preventing graft failure.
Area of Science:
- Vascular Biology
- Oligonucleotide Therapeutics
- Surgical Research
Background:
- Intimal hyperplasia is a major cause of vein graft failure after bypass surgery.
- Proliferating cell nuclear antigen (PCNA) plays a critical role in cell proliferation and the development of intimal hyperplasia.
Purpose of the Study:
- To investigate the efficacy of antisense oligonucleotide targeting PCNA in preventing vein graft intimal hyperplasia in vivo.
- To assess the impact of localized antisense PCNA administration on graft morphology.
Main Methods:
- A rabbit carotid interposition bypass graft model was established using external jugular veins.
- Grafts were treated with antisense oligonucleotide to PCNA, nonsense oligonucleotide, or pluronic gel alone (controls).
- Morphological and videomorphometric analyses were performed 28 days post-surgery.
Main Results:
- Antisense PCNA treatment resulted in a 26% reduction in intimal thickness compared to control and nonsense oligonucleotide groups.
- No significant changes were observed in medial thickness.
- Control and nonsense oligonucleotide groups showed similar intimal thickness.
Conclusions:
- Localized, single application of antisense oligonucleotide to PCNA effectively reduces experimental vein graft intimal hyperplasia.
- Targeting PCNA is a viable therapeutic strategy for mitigating intimal hyperplasia in vascular grafts.