期刊
CIRCULATION
卷 107, 期 20, 页码 2623-2629出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.CIR.0000066911.03770.8D
关键词
transplantation; gene therapy; grafting; arteriosclerosis; remodeling
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. Methods and 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-beta(1). 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.
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