Cardiovascular Research Advance Access [Accepted Manuscript] published online on May 29, 2008
Cardiovascular Research, 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, Germany
2 Institute of Physiology and Pathophysiology, University of Heidelberg, Germany
3 Department of Pathology, Saarland University Hospital, Homburg, Germany
Address for correspondence: Dr. Markus Hecker Institute of Physiology and Pathophysiology Division of Cardiovascular Physiology University of Heidelberg Im Neuenheimer Feld 326 69120 Heidelberg, Germany Tel.: ++49 6221 544035 Fax: ++49 6221 544038 Email 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 transcription factors AP-1 or 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 PCR 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 tumor necrosis factor-
/interferon-
-stimulated expression of CD40 in rat native endothelial cells.
Conclusions: Treating donor hearts with decoy ODNs neutralizing AP-1 or STAT-1 at the time of transplantation prevents up-regulation of CD40 expression in the graft coronary arteries and effectively inhibits CAV.
KEYWORDS Heart; transplantation; arteriosclerosis; decoy oligodeoxynucleotide; CD40
Time for primary review: 26 days
* Both authors contributed equally to this work.
This work was supported by the Deutsche Forschungsgemeinschaft, Collaborative Research Centers 405 and 547, and Research Training Group 534.