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(Circulation. 2005;112:76-83.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

Bcl-xL Gene Transfer Inhibits Bax Translocation and Prolongs Cardiac Cold Preservation Time in Rats

Jianhua Huang, MD; Kiminori Nakamura, DDS, PhD; Yoshinori Ito, MD; Takeshi Uzuka, MD; Masayuki Morikawa, MD, PhD; Sachie Hirai, BS; Kei Tomihara, DDS; Toshihiro Tanaka, MD, PhD; Yukari Masuta, BS; Keiji Ishii, MD; Kazunori Kato, PhD; Hirofumi Hamada, MD, PhD

From the Department of Molecular Medicine (J.H., K.N., Y.I., S.H., K.T., T.T., Y.M., K.I., K.K., H.H.), the Division of Gene Therapy (Y.I., H.H.), and the Department of Thoracic and Cardiovascular Surgery (T.U., M.M.), Sapporo Medical University, Sapporo, Japan.

Correspondence to Hirofumi Hamada, MD, PhD, Department of Molecular Medicine, Sapporo Medical University, South 1, West 17, Chuo-ku, Sapporo, 060-8556, Japan. E-mail hhamada{at}sapmed.ac.jp

Received June 27, 2004; de novo received January 12, 2005; revision received February 25, 2005; accepted March 8, 2005.

Background— Apoptosis is an important cause of early graft loss after heart transplantation. Bcl-xL was reported to protect the heart against normothermic ischemia and reperfusion injury. In this study, we determined whether overexpression of Bcl-xL could inhibit tissue injury resulting from prolonged cold preservation followed by warm reperfusion of heart transplants.

Methods and Results— Lewis rat hearts were transduced with an adenovirus vector harboring Bcl-xL cDNA (AxCAhBclxL) 4 days before collection of tissue. After preservation in University of Wisconsin solution at 4°C for 24 hours, the heart was either perfused with a Langendorff device ex vivo or used for heterotopic heart transplantation in vivo. Bcl-xL gene transfer significantly reduced the infarct size (23.0±2.6% versus 47.7±7.0% in saline control and 48.6±6.1% in vector control, P<0.01) after 2-hour reperfusion at 37°C with the Langendorff device and significantly decreased creatine kinase release (0.82±0.27 IU, versus 1.57±0.33 and 1.50±0.37 IU in saline and vector controls, respectively; P<0.05). In heart transplantation, overexpresson of Bcl-xL inhibited Bax translocation from the cytosol to the mitochondria, resulting in decreased cytochrome c release from the mitochondria; it also significantly decreased cardiac cell apoptosis and improved graft survival rate after long cold preservation, followed by warm reperfusion.

Conclusions— Bcl-xL gene transfer inhibited the translocation of Bax and prolonged the cold preservation time of cardiac transplants. This may be a potential therapeutic method in clinical practice.

Key Words: gene therapy • ischemia • reperfusion • transplantation • apoptosis

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