Prevention of chronic deterioration of heart allograft by recombinant adeno-associated virus-mediated heme oxygenase-1 gene transfer.
BACKGROUND
Allograft deterioration is the major obstacle to organ transplantation as a long-term treatment of end-stage heart failure. In this study, we transduced the antioxidant gene, heme oxygenase-1 (HO-1), to heart grafts using a recombinant adeno-associated viral vector (rAAV) in a rat heart transplantation model and investigated its potentiality in prevention of chronic graft deterioration.


RESULTS
rAAV/HO-1 was administered to heart grafts through the coronary arteries during cold preservation. We investigated the expression patterns and activities of transgene, graft survival, graft histomorphology, and relevance of HO-1 expression on graft survival and chronic graft deterioration by itself. Long-term allograft survival can be achieved by rAAV/HO-1-mediated stable transgene expression. The development of graft arteriosclerosis and interstitial fibrosis was prevented in rAAV/HO-1-transduced allografts on day 100. rAAV/HO-1-mediated long-term graft protection was accompanied by remarkable downregulation of the intragraft mRNA level of macrophage migration inhibitory factor, tumor necrosis factor-alpha, and transforming growth factor-beta1. Blockage of HO activities by zinc protoporphyrin IX at different posttransplant phases showed that the stable expression of HO-1 is a prerequisite for both survival of grafts and prevention of graft arteriosclerosis.


CONCLUSIONS
rAAV/HO-1 gene transfer represents a novel therapeutic approach to prevent chronic allograft deterioration in clinical heart transplantation.
Tsui
Tung-Yu
TY
Department of Surgery, University of Hong Kong Medical Centre, Queen Mary Hospital, 102 Pokfulam Rd, Hong Kong. tytsui@hkucc.hku.hk
Wu
Xiaobing
X
Lau
Chi-Keung
CK
Ho
David W Y
DW
Xu
Tao
T
Siu
Yeung-Tung
YT
Fan
Sheung-Tat
ST
D000818:Animals; D001161:Arteriosclerosis / Q000473:pathology / Q000517:prevention & control; D000229:Dependovirus / Q000235:genetics; D018450:Disease Progression; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005355:Fibrosis / Q000473:pathology / Q000517:prevention & control; D020869:Gene Expression Profiling; D018014:Gene Transfer Techniques; D006085:Graft Survival / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006321:Heart / Q000187:drug effects; D016027:Heart Transplantation / Q000009:adverse effects*; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D051547:Heme Oxygenase-1; D066298:In Vitro Techniques; D023421:Models, Animal; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D019076:Transgenes; D014184:Transplantation, Homologous / Q000473:pathology
D004791:Enzyme Inhibitors; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1