Overexpression of human copper/zinc superoxide dismutase (SOD1) suppresses ischemia-reperfusion injury and subsequent development of graft coronary artery disease in murine cardiac grafts

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Abstract

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-2b) 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-aα, 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-2bm12) 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.

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Tanaka, M., Mokhtari, G. K., Terry, R. D., Balsam, L. B., Lee, K. H., Kofidis, T., … Robbins, R. C. (2004). Overexpression of human copper/zinc superoxide dismutase (SOD1) suppresses ischemia-reperfusion injury and subsequent development of graft coronary artery disease in murine cardiac grafts. Circulation, 110(11 SUPPL.). https://doi.org/10.1161/01.CIR.0000138390.81640.54

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