Attenuation of oxidative stress in HL-1 cardiomyocytes improves mitochondrial function and stabilizes Hif-1alpha.
HL-1 cardiomyocytes were subjected to simulated hypoxia, in the presence of cobalt chloride, which resulted in reduction of cell viability and induction of DNA laddering, indicating the activation of the apoptotic cascade. In the presence of trolox, ascorbic acid, melatonin and the hybrid compound of trolox and lipoic acid (LaT 3a), cell viability was increased, with LaT 3a exhibiting the best effect. Antioxidant treatment restored ATP levels, abolished laddering of DNA, abrogated MPTP opening, Bax translocation to the mitochondria and cytochrome c release to the cytoplasm. Moreover, severe hypoxia, was found to destabilize hypoxia inducible factor-1alpha (Hif-1alpha) mRNA. Reduction of oxidative stress attenuated this effect, implying a possible anti-apoptotic action of the master regulator of hypoxia response. Our data suggest that antioxidants can maintain cell function and survival by inhibiting the mitochondrial apoptotic pathway and stabilizing Hif-1alpha.
Vassilopoulos
Athanassios
A
Department of Animal and Human Physiology, School of Biology, Faculty of Sciences, University of Athens, Panepistimioupolis, 15784 Athens, Greece.
Papazafiri
Panagiota
P
D000255:Adenosine Triphosphate / Q000378:metabolism; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D015687:Cell Hypoxia; D002460:Cell Line; D003035:Cobalt / Q000633:toxicity; D045304:Cytochromes c / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007473:Ion Channels / Q000378:metabolism; D008929:Mitochondria, Heart / Q000502:physiology*; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000648:ultrastructure; D018384:Oxidative Stress / Q000187:drug effects*; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
D000975:Antioxidants; C494826:BAX protein, human; C494811:BCL2L1 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D003035:Cobalt; D000255:Adenosine Triphosphate; D045304:Cytochromes c; C018021:cobaltous chloride