Cardiovascular Research Advance Access originally published online on May 29, 2008
Cardiovascular Research 2008 79(4):698-705; doi:10.1093/cvr/cvn135
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AP-1 and STAT-1 decoy oligodeoxynucleotides attenuate transplant vasculopathy in rat cardiac allografts
1 Department of Internal Medicine, University Hospital Giessen, Giessen, Germany
2 Division of Cardiovascular Physiology, Institute of Physiology and Pathophysiology, University of Heidelberg, Im Neuenheimer Feld 326, 69120 Heidelberg, Germany
3 Department of Pathology, Saarland University Hospital, Homburg, Germany
* Corresponding author. Tel: +49 6221 54 4035; fax: +49 6221 54 4038. E-mail address: hecker{at}physiologie.uni-hd.de
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-
-/interferon-
-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.
KEYWORDS Heart; Transplantation; Atherosclerosis; Decoy oligodeoxynucleotide; CD40
Time for primary review: 26 days
Both authors contributed equally to this work.