Document Detail


AP-1 and STAT-1 decoy oligodeoxynucleotides attenuate transplant vasculopathy in rat cardiac allografts.
MedLine Citation:
PMID:  18511434     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Thomas H W Stadlbauer; Andreas H Wagner; Hans Hölschermann; Sandra Fiedel; Horst Fingerhuth; Harald Tillmanns; Rainer M Bohle; Markus Hecker
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-05-29
Journal Detail:
Title:  Cardiovascular research     Volume:  79     ISSN:  0008-6363     ISO Abbreviation:  Cardiovasc. Res.     Publication Date:  2008 Sep 
Date Detail:
Created Date:  2008-08-20     Completed Date:  2008-10-03     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  0077427     Medline TA:  Cardiovasc Res     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  698-705     Citation Subset:  IM    
Affiliation:
Department of Internal Medicine, University Hospital Giessen, Giessen, Germany.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antigens, CD40 / metabolism
Coronary Artery Disease / etiology,  genetics,  metabolism,  pathology,  prevention & control*
Coronary Vessels / immunology,  metabolism*,  pathology
Endothelial Cells / metabolism
Gene Therapy / methods*
Heart Transplantation / adverse effects*
Interferon-gamma / metabolism
Male
Oligonucleotides / metabolism*
Rats
Rats, Inbred Lew
Rats, Inbred WF
STAT1 Transcription Factor / genetics,  metabolism*
Time Factors
Transcription Factor AP-1 / genetics,  metabolism*
Transplantation, Homologous
Transplantation, Isogeneic
Tumor Necrosis Factor-alpha / metabolism
Tunica Media / metabolism
Chemical
Reg. No./Substance:
0/Antigens, CD40; 0/Oligonucleotides; 0/STAT1 Transcription Factor; 0/Stat1 protein, rat; 0/Transcription Factor AP-1; 0/Tumor Necrosis Factor-alpha; 82115-62-6/Interferon-gamma

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