AP-1 and STAT-1 decoy oligodeoxynucleotides attenuate transplant vasculopathy in rat cardiac allografts.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Department of Internal Medicine, University Hospital Giessen, Giessen, Germany.
Thomas H W
TH
Stadlbauer
Andreas H
AH
Wagner
Hans
H
Hölschermann
Sandra
S
Fiedel
Horst
H
Fingerhuth
Harald
H
Tillmanns
Rainer M
RM
Bohle
Markus
M
Hecker
D000818:Animals; D019013:CD40 Antigens / Q000378:metabolism; D003324:Coronary Artery Disease / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D003331:Coronary Vessels / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D016027:Heart Transplantation / Q000009:adverse effects*; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D009841:Oligonucleotides / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D011920:Rats, Inbred WF; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D017540:Tunica Media / Q000378:metabolism
D019013:CD40 Antigens; D009841:Oligonucleotides; D050794:STAT1 Transcription Factor; C494081:Stat1 protein, rat; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma