Oxygenated Perfluorochemicals Improve Cell Survival during Reoxygenation by Pacifying Mitochondrial Activity

Arab, Amina; Kuemmerer, Klaus; Wang, Jin; Bode, Christoph; Hehrlein, Christoph

doi:10.1124/jpet.107.133710

Cited by 11 publications

(15 citation statements)

References 34 publications

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“…This result was consistent with previous findings after inhibition of oxidative phosphorylation (25). In addition, NO inhibition of ETC has been proven protective for the mitochondrial membrane potential (12), a phenomenon that we have shown previously for oxygen delivery (14). Thomas et al (26) demonstrated that NO inhibition of ETC might extend the zone of tissue oxygenation in vivo.…”

Section: Discussionsupporting

confidence: 82%

“…In our previous paper, we presented information about cell viability of ischemic cardiomyocytes (14). The rationale for using cardiomyocytes after prolonged ischemia in this model was to understand why patients with myocardial infarction subjected to normoxic reperfusion after 12 h often do not experience complete myocardial salvage.…”

Section: Discussionmentioning

confidence: 99%

“…Model of Hypoxia and Reoxygenation-Ischemia was mimicked by exposing cardiomyocytes (seeding density, 3000 cells/ cm 2 ) to a low oxygen atmosphere (pO 2 Ͻ40 mm Hg) as described previously (14). Hypoxia was maintained by continuous infusion of 95% N 2 /5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

“…1) and was calculated as described previously (14). In brief, we added liquid oxygenated PFC to ischemic cardiomyocytes cultured in cell medium to induce hyperoxic conditions around the cells.…”

Section: Methodsmentioning

confidence: 99%

“…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). However, it is unclear how hyperoxia affects NO production in ischemic cardiomyocytes.…”

mentioning

confidence: 99%

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Transient Hyperoxic Reoxygenation Reduces Cytochrome c Oxidase Activity by Increasing Superoxide Dismutase and Nitric Oxide

Arab

Wang

Bausch

et al. 2010

Journal of Biological Chemistry

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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 ≈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.Oxygen therapies have been available for more than 100 years (1) and recently have been shown to be neuroprotective in a dose-dependent fashion (2). One mode of hyperoxic treatment is applying oxygenated perfluorocarbons (PFC) 2 locally to tissues (3). Previously, we have characterized the effects of different hyperoxic conditions on cell viability of ischemic human cardiomyocytes and their mitochondria by the addition of oxygenated PFC to the cell medium (see Fig. 1). Mitochondria have a key function in cardiomyocyte survival after ischemia and reperfusion because mitochondrial respiration produces more than 90% of the heart's energy by oxidative phosphorylation (4).Conversely, oxidative phosphorylation is a central site of reactive oxygen species production in the heart (5-7). Oxidative phosphorylation along with NADPH oxidase form the major sources of superoxide in myocytes (8) that may induce irreversible cellular damage and cell death (9). 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. Sandau et al. (13) have shown that NO production by inducible nitric-oxide synthase (iNOS) can mimic a hypoxic response under normoxia. We have shown previously that hypoxia-inducible factors 1␣ and 2␣ are stabilized after hyperoxic reoxyge...

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Transient Hyperoxic Reoxygenation Reduces Cytochrome c Oxidase Activity by Increasing Superoxide Dismutase and Nitric Oxide

Arab

Wang

Bausch

et al. 2010

Journal of Biological Chemistry

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STEMI therapy: Normoxic reperfusion is not good enough

Hehrlein

2011

Cathet Cardio Intervent

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Ischemia-induced Copper Loss and Suppression of Angiogenesis in the Pathogenesis of Myocardial Infarction

Kang

2012

Cardiovasc Toxicol

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Myocardial ischemia is a primary cause for the loss of vital components such as cardiomyocytes in the heart, leading to myocardial infarction and eventual cardiac dysfunction or heart failure. Suppressed angiogenesis plays a determinant role in the pathogenesis of myocardial infarction. In response to myocardial ischemia, hypoxia-inducible factor-1α and 2α (HIF-1α and HIF-2α) accumulate in cardiomyocytes and other cell types. This would up-regulate the expression of genes involved in angiogenesis such as vascular endothelial growth factor (VEGF); however, it is often observed that the angiogenic capacity is suppressed rather than enhanced. Ischemic toxicity, which has not been fully recognized, is highly responsible for the compromised angiogenic capacity. One of the toxic effects resulting from myocardial ischemia is the loss of copper content in the heart. Although the reason for this loss has not been elucidated, the essential role of copper in the regulation of HIF-1 transcriptional activity has been described. Copper does not affect the accumulation of HIF-1α in the cell, but is required for the HIF-1 transcriptional complex formation and its interaction with the hypoxia-responsive element in target genes. Copper supplementation can stimulate the transcriptional activity of HIF-1 and restore angiogenic capacity, leading to increased capillary density in the heart. The recognition of ischemic toxicity and the effort to overcome the toxic effect would help develop alternative approaches in the treatment of ischemic heart disease.

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Oxygenated Perfluorochemicals Improve Cell Survival during Reoxygenation by Pacifying Mitochondrial Activity

Cited by 11 publications

References 34 publications

Transient Hyperoxic Reoxygenation Reduces Cytochrome c Oxidase Activity by Increasing Superoxide Dismutase and Nitric Oxide

Transient Hyperoxic Reoxygenation Reduces Cytochrome c Oxidase Activity by Increasing Superoxide Dismutase and Nitric Oxide

STEMI therapy: Normoxic reperfusion is not good enough

Ischemia-induced Copper Loss and Suppression of Angiogenesis in the Pathogenesis of Myocardial Infarction

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