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Updated: Jul 4, 2026
Orthotopic Aortic Transplantation: A Rat Model to Study the Development of Chronic Vasculopathy
Published on: December 4, 2010
AP-1 and STAT-1 decoy oligodeoxynucleotides attenuate transplant vasculopathy in rat cardiac allografts
Thomas H W Stadlbauer1, Andreas H Wagner, Hans Hölschermann
1Department of Internal Medicine, University Hospital Giessen, Giessen, Germany.
Aims:
Cardiac allograft vasculopathy (CAV) continues to be an unsolved clinical problem requiring the development of new therapeutic strategies. We have previously demonstrated that ex vivo donor allograft treatment with decoy oligodeoxynucleotides (ODN) targeting the transcription factors, activator protein-1 (AP-1) or signal transducer and activator of transcription-1 (STAT-1), delays acute rejection and prolongs cardiac allograft survival. Here, we investigated whether this treatment regime also prevents the occurrence of CAV in a fully allogeneic rat heart transplantation model.
Methods And Results:
Wistar-Furth rat cardiac allografts were perfused ex vivo with AP-1 decoy ODN, STAT-1 decoy ODN, or buffer solution and transplanted into the abdomen of Lewis rats immunosuppressed with cyclosporine. Treatment with both decoy ODNs but not vehicle significantly attenuated the incidence and severity of CAV. Laser-assisted microdissection/real-time polymerase chain reaction as well as immunohistochemistry analyses revealed a significant increase in CD40 abundance in the coronary endothelial cells and medial smooth muscle cells on day 1 post transplantation which was virtually abolished upon AP-1 or STAT-1 decoy ODN treatment. While the AP-1 decoy ODN primarily attenuated basal CD40 expression, the STAT-1 decoy ODN suppressed tumour necrosis factor-alpha-/interferon-gamma-stimulated expression of CD40 in rat native endothelial cells.
Conclusion:
Treating donor hearts with decoy ODNs neutralizing AP-1 or STAT-1 at the time of transplantation prevents upregulation of CD40 expression in the graft coronary arteries and effectively inhibits CAV.
Insights
Ex vivo treatment of donor hearts with decoy oligodeoxynucleotides (ODN) targeting activator protein-1 (AP-1) or signal transducer and activator of transcription-1 (STAT-1) effectively prevents cardiac allograft vasculopathy (CAV) by inhibiting CD40 upregulation.
Area of Science:
- Transplantation immunology
- Molecular biology
- Cardiovascular research
Background:
- Cardiac allograft vasculopathy (CAV) is a major cause of late graft loss after heart transplantation.
- Current therapeutic strategies for CAV are limited.
- Previous studies showed that ex vivo donor allograft treatment with decoy oligodeoxynucleotides (ODN) targeting activator protein-1 (AP-1) or signal transducer and activator of transcription-1 (STAT-1) can delay acute rejection and prolong graft survival.
Purpose of the Study:
- To investigate the efficacy of ex vivo donor allograft treatment with AP-1 or STAT-1 decoy ODN in preventing CAV.
- To determine the effect of this treatment on CD40 expression in the allograft.
Main Methods:
- A fully allogeneic rat heart transplantation model was used.
- Donor hearts were perfused ex vivo with AP-1 decoy ODN, STAT-1 decoy ODN, or buffer solution before transplantation.
- Immunosuppression was achieved with cyclosporine.
- Cardiac allograft vasculopathy (CAV) incidence and severity were assessed.
- CD40 expression in coronary endothelial cells and smooth muscle cells was analyzed using laser-assisted microdissection/real-time polymerase chain reaction and immunohistochemistry.
Main Results:
- Treatment with both AP-1 and STAT-1 decoy ODN significantly attenuated the incidence and severity of CAV compared to the buffer control.
- Decoy ODN treatment virtually abolished the significant increase in CD40 abundance observed on day 1 post-transplantation.
- AP-1 decoy ODN primarily reduced basal CD40 expression, while STAT-1 decoy ODN suppressed tumor necrosis factor-alpha/interferon-gamma-stimulated CD40 expression.
Conclusions:
- Ex vivo treatment of donor hearts with decoy ODN targeting AP-1 or STAT-1 effectively prevents CAV.
- This therapeutic strategy inhibits the upregulation of CD40 expression in graft coronary arteries.
- Decoy ODN treatment represents a promising novel therapeutic approach for preventing CAV.
