Abstract
Increased levels of extracellular superoxide dismutase (ecSOD) induced by preconditioning or gene therapy protect the heart from ischemia/reperfusion injury. To elucidate the mechanism responsible for this action, we studied the effects of increased superoxide scavenging on nitric oxide (NO) bioavailability in a cardiac myocyte-specific ecSOD transgenic (Tg) mouse. Results indicated that ecSOD overexpression increased cardiac myocyte-specific ecSOD activity 27.5-fold. Transgenic ecSOD was localized to the sarcolemma and, notably, the cytoplasm of cardiac myocytes. Ischemia/reperfusion injury was attenuated in ecSOD Tg hearts, in which infarct size was decreased and LV functional recovery was improved. Using the ROS spin trap, DMPO, electron paramagnetic resonance (EPR) spectroscopy demonstrated a significant decrease in ROS in Tg hearts during the first 20 min of reperfusion. This decrease in ROS was accompanied by an increase in NO production determined by EPR using the NO spin trap, Fe-MGD. Attenuated ROS in ecSOD Tg myocytes was also supported by decreased production of peroxynitrite (ONOO−). Increased NO bioavailability was confirmed by attenuated guanylate cyclase-dependent (p-VASP) signaling. In conclusion, attenuation of ROS levels by cardiac-specific ecSOD overexpression increases NO bioavailability in response to ischemia/reperfusion and protects against reperfusion injury. These findings are the first to demonstrate increased NO bioavailability with attenuation of ROS by direct measurement of these reactive species (EPR, reactive fluorescent dyes) with cardiac-specific ecSOD expression. This is also the first indication that the predominantly extracellular SOD isoform is capable of cytosolic localization that affects myocardial intracellular signal transduction and function.Electronic supplementary materialThe online version of this article (doi:10.1007/s00395-012-0305-1) contains supplementary material, which is available to authorized users.
Highlights
Extracellular superoxide dismutase has been found to play an important role in attenuating the effects of the reactive oxygen species (ROS) such as superoxide anion (O2-), after ischemia/reperfusion injury
Extracellular superoxide dismutase gene therapy and ischemic preconditioning with increased extracellular superoxide dismutase (ecSOD) have been shown to protect the myocardium from ischemia/reperfusion injury
To elucidate the mechanisms by which increased nitric oxide (NO) and decreased ROS may mediate protection against ischemia/reperfusion injury, we examined NO signaling via a guanylate cyclase (GC)-dependent pathway by measuring Ser239 phosphorylation and activation of the cGMP-dependent protein kinase (PKG) substrate vasodilator-stimulated protein (VASP) [55, 56]
Summary
Extracellular superoxide dismutase (ecSOD) has been found to play an important role in attenuating the effects of the reactive oxygen species (ROS) such as superoxide anion (O2-), after ischemia/reperfusion injury. Increased oxidative stress caused by ischemia/reperfusion, chronic load, or heart failure leads to myocardial damage and decreased function [6]. EcSOD, which catalyzes the dismutation of O2- to H2O2 and O2, is a key enzyme that maintains relatively low levels of this important oxygen-derived radical. Overexpression of ecSOD or treatment with SOD mimetics [31, 32, 60] has been shown to attenuate oxidative stress and to mitigate tissue dysfunction in cardiovascular disease. Studies with targeted deletion of ecSOD support the antioxidant role of this enzyme, as the absence of this enzyme was found to exacerbate myocardial dysfunction after myocardial infarction or doxorubicin treatment [29, 59]
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