Abstract
ecSOD function has prototypically been associated with the extracellular space due to its secretion and localization to the extracellular matrix. A myocyte-specific ecSOD transgenic mouse has shown that it can also be localized to the myocyte intracellular compartment and is capable of attenuating Reactive oxygen species (ROS) formation and increasing NO bioavailability after ischemia reperfusion. Here, the subcellular localization of transgenic ecSOD was further defined by subcellular fractionation, immunofluorescent confocal microscopy, and Western analysis. Its impact on mitochondrial function was assessed by mitochondrial permeability transition (MPT). ecSOD was found to exist in cytosolic and nuclear fractions in addition to membrane. Colocalization of ecSOD with myocardial mitochondria was further demonstrated by confocal microscopy and subcellular fractionation of mitochondria and Western analysis. Isolated ventricular myocytes from cardiac-specific transgenic ecSOD mice were protected from hypoxia reoxygenation injury. Increased ecSOD colocalization to myocardial mitochondria in ecSOD Tg hearts limited MPT in response to Ca2+ challenge. These results demonstrate that ecSOD is not restricted to the extracellular space and can alter MPT response to Ca2+ suggesting mitochondrial localization of ecSOD can affect key mitochondrial functions such as MPT which are integral to cell survival.
Highlights
Reactive oxygen species (ROS), including superoxide anion (O−2 ), are an ubiquitous product of several cellular processes
EcSOD Tg CARDIAC MYOCYTES ARE RESISTANT TO HYPOXIA/REOXYGENATION INJURY Our previous studies have shown that cardiac specific ecSOD overexpression protects the heart from ischemia reperfusion injury supporting earlier studies showing ecSOD is cardioprotective (Obal et al, 2012)
In defining the role of ecSOD in protecting the myocardium from ischemia reperfusion injury we extend our current understanding of its actions using the cardiac specific ecSOD Tg mouse
Summary
Reactive oxygen species (ROS), including superoxide anion (O−2 ), are an ubiquitous product of several cellular processes. ROS are important in signal transduction through the activation of NADPH oxidases and by several other mechanisms (Griendling et al, 1994) including, xanthine oxidase (Ekelund et al, 1999), nitric oxide synthase (Xia et al, 1998), a product of cellular metabolism, and may be increased as a consequence of myocardial ischemia reperfusion, with tissue injury, and other pathologies (Sawyer et al, 2002). Three SODs, extracellular (ecSOD), manganese (MnSOD), and copper-zinc (CuZnSOD) are present in cells to varying degrees and differentially localized to specific compartments that orchestrate the dismutation of O−2 to hydrogen peroxide (H2O2) and O2. EcSOD expression in this mouse was found to be elevated in both extracellular and intracellular compartments We extend these findings by further characterizing the intracellular localization of ecSOD and demonstrate the functional consequences of mitochondrial ecSOD
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