AP-1 and STAT-1 decoy oligodeoxynucleotides attenuate transplant vasculopathy in rat cardiac allografts
Identifieur interne : 000644 ( Main/Exploration ); précédent : 000643; suivant : 000645AP-1 and STAT-1 decoy oligodeoxynucleotides attenuate transplant vasculopathy in rat cardiac allografts
Auteurs : Thomas H. W. Stadlbauer [Allemagne] ; Andreas H. Wagner [Allemagne] ; Hans Hlschermann [Allemagne] ; Sandra Fiedel [Allemagne] ; Horst Fingerhuth [Allemagne] ; Harald Tillmanns [Allemagne] ; Rainer M. Bohle [Allemagne] ; Markus Hecker [Allemagne]Source :
- Cardiovascular Research [ 0008-6363 ] ; 2008-09-01.
Abstract
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.
Url:
DOI: 10.1093/cvr/cvn135
Affiliations:
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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.</div></front></TEI><affiliations><list><country><li>Allemagne</li></country><region><li>Bade-Wurtemberg</li><li>District de Karlsruhe</li></region><settlement><li>Heidelberg</li></settlement></list><tree><country name="Allemagne"><noRegion><name sortKey="Stadlbauer, Thomas H W" sort="Stadlbauer, Thomas H W" uniqKey="Stadlbauer T" first="Thomas H. W." last="Stadlbauer">Thomas H. W. Stadlbauer</name></noRegion><name sortKey="Bohle, Rainer M" sort="Bohle, Rainer M" uniqKey="Bohle R" first="Rainer M." last="Bohle">Rainer M. Bohle</name><name sortKey="Fiedel, Sandra" sort="Fiedel, Sandra" uniqKey="Fiedel S" first="Sandra" last="Fiedel">Sandra Fiedel</name><name sortKey="Fingerhuth, Horst" sort="Fingerhuth, Horst" uniqKey="Fingerhuth H" first="Horst" last="Fingerhuth">Horst Fingerhuth</name><name sortKey="Hecker, Markus" sort="Hecker, Markus" uniqKey="Hecker M" first="Markus" last="Hecker">Markus Hecker</name><name sortKey="Hecker, Markus" sort="Hecker, Markus" uniqKey="Hecker M" first="Markus" last="Hecker">Markus Hecker</name><name sortKey="Hlschermann, Hans" sort="Hlschermann, Hans" uniqKey="Hlschermann H" first="Hans" last="Hlschermann">Hans Hlschermann</name><name sortKey="Tillmanns, Harald" sort="Tillmanns, Harald" uniqKey="Tillmanns H" first="Harald" last="Tillmanns">Harald Tillmanns</name><name sortKey="Wagner, Andreas H" sort="Wagner, Andreas H" uniqKey="Wagner A" first="Andreas H." last="Wagner">Andreas H. Wagner</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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