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(Circulation. 2004;110:II-200 – II-206.)
© 2004 American Heart Association, Inc.

Cardiac Transplantation and Surgery for Congestive Heart Failure

Overexpression of Human Copper/Zinc Superoxide Dismutase (SOD1) Suppresses Ischemia–Reperfusion Injury and Subsequent Development of Graft Coronary Artery Disease in Murine Cardiac Grafts

Masashi Tanaka, MD; Golnaz K. Mokhtari; Raya D. Terry; Leora B. Balsam, MD; Keun-Ho Lee, PhD; Theo Kofidis, MD; Philip S. Tsao, PhD; Robert C. Robbins, MD

From Department of Cardiothoracic Surgery (M.T., R.D.T., L.B.B., T.K., R.C.R.), Department of Cardiovascular Medicine (K.-H.L., P.S.T.), Stanford University Medical Center, Stanford, Calif.

Correspondence to Masashi Tanaka, MD, Department of Cardiothoracic Surgery, Stanford University School of Medicine, Falk Cardiovascular Research Center, Stanford, CA 94305-5407. E-mail masashi{at}omiya.jichi.ac.jp

Background— Ischemia–reperfusion injury is an important risk factor for graft coronary artery disease (GCAD). We hypothesized that overexpression of SOD1 in donor hearts would suppress ischemia—reperfusion injury and thereby reduce GCAD.

Methods and Results— In one series, donor hearts of C57BL/6 (H-2^b) transgenic mice overexpressing human SOD1 or C57BL/6 wild-type mice were heterotopically transplanted into C57BL/6 recipients and procured after 4 hours of reperfusion (n=6 each). Superoxide, TNF-, and MCP-1/CCL2 production were significantly reduced in the SOD1 transgenic donor heart recipients, and graft injury determined by serum CPK-MB levels was significantly decreased. Cardiomyocyte apoptosis and caspase-3 and caspase-9 activities were significantly decreased in these recipients; caspase-8 activity was unchanged. Fas ligand but not Fas expression was also reduced. In a second series, transgenic and wild-type hearts were transplanted into C-H-2^bm12KhEg (H-2^bm12) recipients, and then procured on day 56 (n=7 each). Cardiac graft beating was significantly better in the SOD1 transgenic donor heart recipients on days 28, 42, and 56 (but not day 14). Significant reduction in luminal narrowing, the intima/media ratio, and the percentage of diseased vessels was seen in the SOD1 transgenic donor heart recipients, and MCP-1/CCL2, ICAM-1, and VCAM-1 production were significantly reduced.

Conclusions— Overexpression of SOD1 attenuates both apoptosis and the inflammatory response during ischemia—reperfusion injury and therefore mitigates against the subsequent development of GCAD.

Key Words: apoptosis • arteriosclerosis • ischemia • reperfusion • transplantation