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Apoptotic Cell Death in Cultured Cardiomyocytes Following Exposure to Low Concentrations of 4-Hydroxy-2-nonenal

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Abstract

Lipid peroxidation (LP), induced by oxidative stress, is associated with degenerative processes. 4-Hydroxy-2-nonenal (HNE), a highly reactive diffusible product of LP, is considered by-product and mediator of oxidative stress. Its level increases under pathological conditions such as cardiovascular diseases. In this study, we partially characterized the mechanisms of HNE-mediated cytotoxicity in cardiomyocytes. After establishing that pathophysiological doses of HNE trigger cell death dependent on the incubation time and dose of HNE (LD50 = 4.4 μM), we tackled the mechanisms that underlie the cell death induced by HNE. Our results indicate that HNE rapidly increases intracellular Ca2+; it also increases the rate of reactive oxygen species generation and causes a loss of mitochondrial membrane potential (ΔΨm) as well as a decrease in the ATP and GSH levels. Such alterations result in the activation of caspase-3 and DNA breakdown, both characteristic features of apoptotic cell death, as well as disruption of the cytoskeleton. Moreover, the nucleophilic compounds N-acetyl-cysteine and β-mercapto-propionyl-glycine, and the synthetic antioxidant Trolox exert a potent antioxidant action against HNE damage; this suggests its use as effective compounds in order to reduce the damage occurred as consequence of cardiovascular disorders in which oxidative stress and hence LP take place.

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Acknowledgments

We are grateful to Dr. Iffath Ghouri and Dr. Jose María Carvajal-González for their helpful discussion and critical reading of the manuscript. Technical and human support provided by Facility of Bioscience Applied Techniques (STAB) of Servicios de Apoyo a la Investigación (SAIUEx) (financed by Universidad de Extremadura, Junta de Extremadura, Ministerio de Ciencia e Innovación, Fondo Europeo de Desarrollo Regional-FEDER). This work was supported by a Grant from the Junta de Extremadura, Spain (PRI06A132 to F. Henao; GRU09056 and GRU10046 to Grupo de Investigación en Enfermedades Neurodegenerativas). M.P.H.-V. had been the recipient of predoctoral fellowships from the Junta de Extremadura (Spain). All Spanish funding is co-sponsored by the European Union FEDER (Fondo Europeo de Desarrollo Regional) program.

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The authors declare that they have not conflict of interest.

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  1. Departamento de Bioquímica y Biología Molecular y Genética, Facultad de Ciencias, Universidad de Extremadura, 06071, Badajoz, Spain

    María P. Hortigón-Vinagre & Fernando Henao

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  1. María P. Hortigón-Vinagre
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  2. Fernando Henao
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Correspondence to Fernando Henao.

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Hortigón-Vinagre, M.P., Henao, F. Apoptotic Cell Death in Cultured Cardiomyocytes Following Exposure to Low Concentrations of 4-Hydroxy-2-nonenal. Cardiovasc Toxicol 14, 275–287 (2014). https://doi.org/10.1007/s12012-014-9251-5

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