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(Circulation. 2003;107:2623.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Prevention of Chronic Deterioration of Heart Allograft by Recombinant Adeno-Associated Virus-Mediated Heme Oxygenase-1 Gene Transfer

Tung-Yu Tsui, MD; Xiaobing Wu, PhD; Chi-Keung Lau, MPhil; David W.Y. Ho, BSc; Tao Xu, MB; Yeung-Tung Siu, MPhil; Sheung-Tat Fan, MD, PhD, FRCS

From the Centre for the Study of Liver Disease and Department of Surgery, University of Hong Kong Medical Centre, Queen Mary Hospital, Pokfulam Road, Hong Kong, and National Laboratory for Molecular Virology and Genetic Engineering (X.W.), Chinese Academy of Preventive Medicine, Beijing, China.

Correspondence to Dr Tung-Yu Tsui, Department of Surgery, University of Hong Kong Medical Centre, Queen Mary Hospital, 102 Pokfulam Rd, Hong Kong. E-mail tytsui{at}hkucc.hku.hk

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-, and transforming growth factor-ß₁. 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.

Key Words: transplantation • gene therapy • grafting • arteriosclerosis • remodeling

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