Overexpression of human copper,zinc-superoxide dismutase (SOD1) prevents postischemic injury

Abstract

Superoxide and superoxide-derived oxidants have been hypothesized to be important mediators of postischemic injury. Whereas copper,zinc-superoxide dismutase, SOD1, efficiently dismutates superoxide, there has been controversy regarding whether increasing intracellular SOD1 expression would protect against or potentiate cellular injury. To determine whether increased SOD1 protects the heart from ischemia and reperfusion, studies were performed in a newly developed transgenic mouse model in which direct measurement of superoxide, contractile function, bioenergetics, and cell death could be performed. Transgenic mice with overexpression of human SOD1 were studied along with matched nontransgenic 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 both myocytes and endothelial cells. In nontransgenic hearts following 30 min of global ischemia a reperfusion-associated burst of superoxide generation was demonstrated by electron paramagnetic resonance spin trapping. However, in the transgenic hearts with overexpression of SOD1 the burst of superoxide generation was almost totally quenched, and this 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 mediator of postischemic injury and that increasing intracellular SOD1 dramatically protects the heart from this injury. Thus, increasing intracellular SOD1 expression may be a highly effective approach to decrease the cellular injury that occurs following reperfusion of ischemic tissues.

The protective effect of cardiac gene transfer of CuZn–sod in comparison with the cardioprotector monohydroxyethylrutoside against doxorubicin-induced cardiotoxicity in cultured cells

“…Others, however, studied the protection of CuZn-sod against hypoxia-reoxygenation damage, which is also free radical mediated. 14,18,32,33 In the present experiment, significant levels of CuZnsod were produced in NeRCaMs at the third day of infection with AdCuZn-sod compared to noninfected cells. However, the occurrence of cellular cytotoxicity limited the MOI of AdCuZn-sod to 25 PFU/cell.…”

“…Previous experiments, showed that only high level of Mn-sod protected against LDH and CK increase in the serum of transgenic mice. 16 Also complete protection was only obtained with a 10-fold increase in CuZn-sod in transgenic mice 32 while less than five-fold increase in sod activity did not fully protect against free radicals produced by doxorubicin 17 or hypoxia/reoxygenation. 14 MonoHER is a semisynthetic flavonoid.…”

Targeted disruption of the glutaredoxin 1 gene does not sensitize adult mice to tissue injury induced by ischemia/reperfusion and hyperoxia

“…This hypothesis is supported by the findings that knockout mice deficient in copper-zinc superoxide dismutase (CuZnSOD) or cellular glutathione peroxidase (Gpx1) are more sensitive to cardiac I/R injury, and transgenic mice overexpressing either of these enzymes exhibit a resistant phenotype [41][42][43][44][45]. Analogously, overexpression of Grx1 in H9c2 cardiomyocyte cells in vitro protects them from H 2 O 2 -induced apoptosis [29], however an in vivo effect of genetic manipulation of Grx1 has not been reported.…”

Mechanisms by which metals promote events connected to neurodegenerative diseases

“…Overexpression of human CuZnSOD in mice, resulting in a 10-fold higher level in both myocytes and endothelial cells, was able to quench a burst of superoxide (electron probe resonance [EPR] detection) and reduce functional damage following 30 min global ischemia [105]. These results suggest that superoxide is an important factor in protecting against postischemic injury.…”