Abstract 10138: Extracellular Superoxide Dismutase (ecSOD) is Essential for Ischemic Preconditioning (PC): Studies in ecSOD Null and Cardiac Specific Overexpressing Mice
Previous studies have demonstrated that ischemic PC upregulates extracellular superoxide dismutase (ecSOD). However, the role of this gene in the protective effect of PC against ischemia/reperfusion injury remains unclear. To elucidate the role of ecSOD, we manipulated the ecSOD gene by using either a null ecSOD mouse (ecSOD KO) or cardiac-specific overexpressing transgenic mice (ecSOD Tg). Immunoreaction analyses demonstrated that ecSOD was robustly expressed in myocardium of ecSOD Tg but not in nontrangenic (NTg) or KO mice (n=3, Fig). In contrast, the protein expression of Cu/Zn-SOD and Mn-SOD did not change (n=3). In WT mice (Group II, n=16), which were preconditioned 24 h earlier with six 4-min coronary occlusion (O)/4-min reperfusion (R) cycles, the size of the infarcts (27.7 ± 2.6% of risk region, Fig) produced by a 30-min O followed by 24 h of R was reduced markedly (by -48%; P < 0.001) compared with sham-preconditioned controls (Group I, 53.5 ± 1.9%, n=10), indicating a late PC effect. In contrast, when ecSOD KO mice (Group IV, n=9) were preconditioned 24 h earlier with the same protocol, infarct size (55.6 ± 3.3%) was not reduced. When ecSOD Tg mice were subjected to a 30-min O and 24 h of R (AMI), the infarct size averaged 35.0 ± 2.8% of the risk region (Group VI, n=14, Fig), indicating that overexpression of the ecSOD gene has a potent cardioprotective effect. Echocardiographic and hemodynamic studies showed no changes on cardiac function in either ecSOD KO or ecSOD Tg mice. These results demonstrate that (i) targeted disruption of the ecSOD gene completely abrogates the infarct-sparing effect of late PC, providing unequivocal molecular genetic evidence for an obligatory role of ecSOD in the cardioprotection afforded by the late phase of ischemic PC; and (ii) selective cardiac-specific overexpression of ecSOD induces a potent cardioprotective effect against MI. Thus, this study identifies a specific protein that mediates the infarct-sparing actions of late PC in vivo.
- © 2011 by American Heart Association, Inc.