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First published on February 27, 2008; DOI: 10.1124/jpet.107.133710

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Received for publication November 15, 2007.
Revised February 22, 2008.
Accepted for publication February 25, 2008.

Oxygenated Perfluorochemicals Improve Cell Survival during Reoxygenation by Pacifying Mitochondrial Activity

Amina Arab 1*, Klaus Kuemmerer 1, Jin Wang 1, Christoph Bode 1, Christoph Hehrlein 1

1 University of Freiburg

* Address correspondence to: E-mail: arab{at}medizin.ukl.uni-freiburg.de

Abstract

Perfluorochemicals (PFCs) are known to provide a unique tool for controlled uptake and delivery of oxygen. We have characterized the effects of incremental oxygen delivery on cell viability of human ischemic cardiomyocytes using chemically inert PFCs as oxygen carrier. We have found that cell viability after prolonged ischemia depends on the dose of oxygen supplementation by oxygenated (ox) PFCs during reoxygenation. While reoxygenation with the transient addition of oxPFCs in high concentrations (2250µM O2 in 0.4µM PFCs) results in decreased cell viability when compared to normoxic reoxygenation, cell survival increases by 30 ± 4% after reoxygenation with moderate oxPFC-concentrations (750µM O2 in 0.1µM PFCs). Immunoblot analysis revealed that oxPFC-supplemented reoxygenation causes marked (16-fold) deactivation of death-associated protein kinase (DAPK) signaling an increase in mitochondrial membrane potential and a decreased steady state level of superoxide by 19 ± 3%. Reoxygenation with oxPFCs is further responsible for a two-fold activation of AMP-activated protein kinase (AMPK) signaling an inadequate ATP supply by oxidative phosphorylation during reoxygenation. Addition of oxPFCs stabilizes both hypoxia-inducible factor (HIF) 1- {alpha} and 2- {alpha} during reoxygenation. Overall, these results indicate that moderate doses of oxPFCs can improve cell survival during reoxygenation causing deactivation of DAPK, upregulation of AMPK and HIF 1- {alpha} and 2- {alpha} stabilization. These effects of oxPFCs are dose-dependent and lead to a stabilization of the mitochondrial membrane potential, decreased steady state levels of superoxide and pacification of mitochondrial activity.


Key words: AMP- activated protein kinase, cell viability, death-associated protein kinase, hypoxia-inducible factor, mitochondria, perfluorochemical




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