Abstract
Oxygen therapies have been shown to be cytoprotective in a dose-dependent fashion. Previously, we have characterized the protective effects of moderate hyperoxia on cell viability of ischemic human cardiomyocytes and their mitochondrial membrane potential by transient addition of oxygenated perfluorocarbons to the cell medium. Now, we report that the activity and expression of cytochrome c oxidase (COX) after prolonged ischemia depend on the amount of oxygen delivered during reoxygenation. Transient hyperoxia during reoxygenation results in a decrease of COX activity by 62 +/- 15% and COX expression by 67 +/- 5%, when hyperoxic tensions of approximately = 300 mm Hg are reached in the cell medium. This decrease in COX expression is prevented by the inhibition of inducible nitric-oxide synthase (iNOS). Immunoblot analysis of ischemic human cardiomyocytes revealed that hyperoxic reoxygenation causes a 2-fold increase of iNOS, leading to a rise in nitric oxide production by 140 +/- 45%. Hyperoxic reoxygenation is further responsible for a 2-fold activation of hydrogen peroxide production and an increase in cytosolic superoxide dismutase expression by 35 +/- 10%. NADPH availability has no effect on the hyperoxia-induced decrease of superoxide. Overall, these results indicate that transient hyperoxic reoxygenation in optimal concentrations increases the level of nitric oxide by activation of iNOS and superoxide dismutase, thereby inducing respiration arrest in mitochondria of ischemic cardiomyocytes.
Highlights
Hydrate; H2O2, hydrogen peroxide; oxidative phosphorylation is a central site of reactive oxygen species production in the heart [5,6,7]
Prolonged Ischemia and Not Moderate Hyperoxia Decreases Cell Viability—We found that the cell viability of cardiomyocytes is decreased after 12 h of ischemia compared with normoxic cells
Transient Hyperoxic Reoxygenation Decreases c oxidase (COX) Activity— We investigated whether a brief treatment of ischemic cardiomyocytes inducing hyperoxic conditions in the cell medium during reoxygenation changes COX activity compared with normoxic conditions
Summary
Hydrate; H2O2, hydrogen peroxide; oxidative phosphorylation is a central site of reactive oxygen species production in the heart [5,6,7]. Nitric oxide (NO) can inhibit oxidative phosphorylation reversibly by blocking cytochrome c oxidase (COX) of the electron transport chain (ETC) [10]. In this way, NO protects myocardial tissue from ischemia and reperfusion injury [11] possibly by defending the mitochondrion to maintain their membrane potential [12] and reducing cytotoxicity of reactive oxygen species. We have shown previously that hypoxia-inducible factors 1␣ and 2␣ are stabilized after hyperoxic reoxygenation with oxygenated PFC and that their stabilization is protective for ischemic human cardiomyocytes [14]. The aim of this study was to characterize the effects of hyperoxia on ischemic cardiomyocytes with regard to changes in oxidative phosphorylation and NO production and in particular by evaluating of the role of iNOS, COX, and the production of reactive oxygen species during reoxygenation
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