OVEREXPRESSION OF HUMAN COPPER,ZINC-SUPEROXIDE DISMUTASE (SOD1) PREVENTS POSTISCHEMIC INJURY

Superoxide and superoxide-derived oxidants have been hypothesized to b e important mediators of postischemic injury. Whereas copper,zinc-supe roxide dismutase, SOD1, efficiently dismutates superoxide, there has b een controversy regarding whether increasing intracellular SOD1 expres sion would protect against or potentiate cellular injury. To determine whether increased SOD1 protects the heart from ischemia and reperfusi on, studies were performed in a newly developed transgenic mouse model in which direct measurement of superoxide, contractile function, bioe nergetics, and cell death could be performed. Transgenic mice with ove rexpression of human SOD1 were studied along with matched nontransgeni c controls. Immunoblotting and immunohistology demonstrated that total SOD1 expression was increased 10-fold in hearts from transgenic mice compared with nontransgenic controls, with increased expression in bot h myocytes and endothelial cells, In nontransgenic hearts following 30 min of global ischemia a reperfusion-associated burst of superoxide g eneration was demonstrated by electron paramagnetic resonance spin tra pping, However, in the transgenic hearts with overexpression of SOD1 t he burst of superoxide generation was almost totally quenched, and thi s was accompanied by a 2-fold increase in the recovery of contractile function, a 2.2-fold decrease in infarct size, and a greatly improved recovery of high energy phosphates compared with that in nontransgenic controls. These results demonstrate that superoxide is an important m ediator of postischemic injury and that increasing intracellular SOD1 dramatically protects the heart from this injury. Thus, increasing int racellular SOD1 expression may be a highly effective approach to decre ase the cellular injury that occurs following reperfusion of ischemic tissues.