A novel heparin-binding, human chimeric, superoxide dismutase improves myocardial preservation and protects from ischemia-reperfusion injury.
BACKGROUND
The plasma membranes of endothelial cells are sites of physiologic injury caused by superoxide attack, whether the radicals are generated within the cell (i.e., from enzymatic sources such as xanthine oxidase or from ischemically injured mitochondria) or are generated within the interstitial spaces by activated neutrophils or macrophages. An extracellular superoxide dismutase (ECSOD) electrostatically bound to endothelial surfaces partially protects against this oxidative attack. To provide a therapeutic equivalent of this ECSOD activity, we evaluated the product of a fusion gene encoding a chimeric manganese SOD (chimeric-SOD) and the carboxyl-terminal 26-amino acid basic "tail" from ECSOD with high affinity for heparin-like proteoglycans on cell surfaces.


METHODS
We tested the chimeric-SOD in isolated rabbit hearts during warm and cold ischemia.


RESULTS
When perfused through an isolated rabbit heart, chimeric-SOD bound to endothelial surfaces and was displaced by a bolus dose of heparin. In an established model of no-flow ischemia followed by reperfusion of the isolated rabbit heart, the chimeric-SOD was as protective as native Mn-SOD or Cu,Zn-SOD, but at doses nearly 2 orders of magnitude lower. In a rabbit-heart preservation model, the chimeric-SOD provided better recovery of function after 4 hours of cold ischemia than did University of Wisconsin cardioplegia solution.


CONCLUSIONS
This chimeric-SOD can bind to cell surfaces and may aid in preventing superoxide-mediated endothelial damage and may function as a rational therapeutic agent for treating free-radical-mediated diseases.
Nelson
Sally K
SK
Webb-Waring Institute for Biomedical Research, Uniuversity of Colorado Health Science Center, 4200 East Ninth Avenue, Box C-321, Denver, CO 80262, USA. sally.nelson@UCHSC.edu
Gao
Bifeng
B
Bose
Swapan
S
Rizeq
Mona
M
McCord
Joe M
JM
D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D005260:Female; D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*; D011336:Probability; D011485:Protein Binding / Q000187:drug effects; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000187:drug effects* / Q000502:physiology; D012680:Sensitivity and Specificity; D013482:Superoxide Dismutase / Q000494:pharmacology*
D011993:Recombinant Fusion Proteins; D006493:Heparin; D013482:Superoxide Dismutase