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Antioxidant network expression abrogates oxidative posttranslational modifications in mice
1Division of Cardiovascular Medicine, The Ohio State University, Columbus, Ohio, USA.
Abstract:
Antioxidant enzymatic pathways form a critical network that detoxifies ROS in response to myocardial stress or injury. Genetic alteration of the expression levels of individual enzymes has yielded mixed results with regard to attenuating in vivo myocardial ischemia-reperfusion injury, an extreme oxidative stress. We hypothesized that overexpression of an antioxidant network (AON) composed of SOD1, SOD3, and glutathione peroxidase (GSHPx)-1 would reduce myocardial ischemia-reperfusion injury by limiting ROS-mediated lipid peroxidation and oxidative posttranslational modification (OPTM) of proteins. Both ex vivo and in vivo myocardial ischemia models were used to evaluate the effect of AON expression. After ischemia-reperfusion injury, infarct size was significantly reduced both ex vivo and in vivo, ROS formation, measured by dihydroethidium staining, was markedly decreased, ROS-mediated lipid peroxidation, measured by malondialdehyde production, was significantly limited, and OPTM of total myocardial proteins, including fatty acid-binding protein and sarco(endo)plasmic reticulum Ca(²+)-ATPase (SERCA)2a, was markedly reduced in AON mice, which overexpress SOD1, SOD3, and GSHPx-1, compared with wild-type mice. These data demonstrate that concomitant SOD1, SOD3, and GSHPX-1 expression confers marked protection against myocardial ischemia-reperfusion injury, reducing ROS, ROS-mediated lipid peroxidation, and OPTM of critical cardiac proteins, including cardiac fatty acid-binding protein and SERCA2a.
Insights
Overexpressing antioxidant enzymes SOD1, SOD3, and glutathione peroxidase-1 protects the heart from ischemia-reperfusion injury by reducing oxidative stress and protein damage.
Area of Science:
- Cardiovascular Biology
- Oxidative Stress Research
- Biochemistry
Background:
- Antioxidant enzymes detoxify reactive oxygen species (ROS) during myocardial stress.
- Previous studies on single antioxidant enzyme genetic alteration show inconsistent results in mitigating ischemia-reperfusion injury.
- Myocardial ischemia-reperfusion injury involves extreme oxidative stress, lipid peroxidation, and protein modification.
Purpose of the Study:
- To investigate if overexpressing an antioxidant network (AON) of SOD1, SOD3, and glutathione peroxidase-1 (GSHPx-1) protects against myocardial ischemia-reperfusion injury.
- To determine if AON overexpression limits ROS formation, lipid peroxidation, and oxidative posttranslational modification (OPTM) of proteins.
Main Methods:
- Utilized both ex vivo and in vivo myocardial ischemia models.
- Evaluated the effect of AON expression on infarct size, ROS formation, lipid peroxidation, and OPTM.
- Measured ROS using dihydroethidium staining and lipid peroxidation via malondialdehyde production.
Main Results:
- AON overexpression significantly reduced infarct size in both ex vivo and in vivo models.
- Markedly decreased ROS formation and ROS-mediated lipid peroxidation were observed in AON mice.
- Significantly reduced OPTM of myocardial proteins, including fatty acid-binding protein and SERCA2a, in AON mice compared to wild-type.
Conclusions:
- Concomitant expression of SOD1, SOD3, and GSHPx-1 provides significant protection against myocardial ischemia-reperfusion injury.
- AON overexpression effectively reduces ROS, lipid peroxidation, and OPTM of critical cardiac proteins.
- Targeting antioxidant networks offers a promising strategy for mitigating cardiac injury.
