Levosimendan inhibits peroxidation in hepatocytes by modulating apoptosis/autophagy interplay.
BACKGROUND:Levosimendan protects rat liver against peroxidative injuries through mechanisms related to nitric oxide (NO) production and mitochondrial ATP-dependent K (mitoKATP) channels opening. However, whether levosimendan could modulate the cross-talk between apoptosis and autophagy in the liver...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2015-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4400069?pdf=render |
| _version_ | 1828938638483783680 |
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| author | Elena Grossini Kevin Bellofatto Serena Farruggio Lorenzo Sigaudo Patrizia Marotta Giulia Raina Veronica De Giuli David Mary Piero Pollesello Rosalba Minisini Mario Pirisi Giovanni Vacca |
| author_facet | Elena Grossini Kevin Bellofatto Serena Farruggio Lorenzo Sigaudo Patrizia Marotta Giulia Raina Veronica De Giuli David Mary Piero Pollesello Rosalba Minisini Mario Pirisi Giovanni Vacca |
| author_sort | Elena Grossini |
| collection | DOAJ |
| description | BACKGROUND:Levosimendan protects rat liver against peroxidative injuries through mechanisms related to nitric oxide (NO) production and mitochondrial ATP-dependent K (mitoKATP) channels opening. However, whether levosimendan could modulate the cross-talk between apoptosis and autophagy in the liver is still a matter of debate. Thus, the aim of this study was to examine the role of levosimendan as a modulator of the apoptosis/autophagy interplay in liver cells subjected to peroxidation and the related involvement of NO and mitoKATP. METHODS AND FINDINGS:In primary rat hepatocytes that have been subjected to oxidative stress, Western blot was performed to examine endothelial and inducible NO synthase isoforms (eNOS, iNOS) activation, apoptosis/autophagy and survival signalling detection in response to levosimendan. In addition, NO release, cell viability, mitochondrial membrane potential and mitochondrial permeability transition pore opening (MPTP) were examined through specific dyes. Some of those evaluations were also performed in human hepatic stellate cells (HSC). Pre-treatment of hepatocytes with levosimendan dose-dependently counteracted the injuries caused by oxidative stress and reduced NO release by modulating eNOS/iNOS activation. In hepatocytes, while the autophagic inhibition reduced the effects of levosimendan, after the pan-caspases inhibition, cell survival and autophagy in response to levosimendan were increased. Finally, all protective effects were prevented by both mitoKATP channels inhibition and NOS blocking. In HSC, levosimendan was able to modulate the oxidative balance and inhibit autophagy without improving cell viability and apoptosis. CONCLUSIONS:Levosimendan protects hepatocytes against oxidative injuries by autophagic-dependent inhibition of apoptosis and the activation of survival signalling. Such effects would involve mitoKATP channels opening and the modulation of NO release by the different NOS isoforms. In HSC, levosimendan would also play a role in cell activation and possible evolution toward fibrosis. These findings highlight the potential of levosimendan as a therapeutic agent for the treatment or prevention of liver ischemia/reperfusion injuries. |
| first_indexed | 2024-12-14T02:46:27Z |
| format | Article |
| id | doaj.art-50e99e563b594d9a874831345ab32285 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-14T02:46:27Z |
| publishDate | 2015-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-50e99e563b594d9a874831345ab322852022-12-21T23:19:53ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01104e012474210.1371/journal.pone.0124742Levosimendan inhibits peroxidation in hepatocytes by modulating apoptosis/autophagy interplay.Elena GrossiniKevin BellofattoSerena FarruggioLorenzo SigaudoPatrizia MarottaGiulia RainaVeronica De GiuliDavid MaryPiero PolleselloRosalba MinisiniMario PirisiGiovanni VaccaBACKGROUND:Levosimendan protects rat liver against peroxidative injuries through mechanisms related to nitric oxide (NO) production and mitochondrial ATP-dependent K (mitoKATP) channels opening. However, whether levosimendan could modulate the cross-talk between apoptosis and autophagy in the liver is still a matter of debate. Thus, the aim of this study was to examine the role of levosimendan as a modulator of the apoptosis/autophagy interplay in liver cells subjected to peroxidation and the related involvement of NO and mitoKATP. METHODS AND FINDINGS:In primary rat hepatocytes that have been subjected to oxidative stress, Western blot was performed to examine endothelial and inducible NO synthase isoforms (eNOS, iNOS) activation, apoptosis/autophagy and survival signalling detection in response to levosimendan. In addition, NO release, cell viability, mitochondrial membrane potential and mitochondrial permeability transition pore opening (MPTP) were examined through specific dyes. Some of those evaluations were also performed in human hepatic stellate cells (HSC). Pre-treatment of hepatocytes with levosimendan dose-dependently counteracted the injuries caused by oxidative stress and reduced NO release by modulating eNOS/iNOS activation. In hepatocytes, while the autophagic inhibition reduced the effects of levosimendan, after the pan-caspases inhibition, cell survival and autophagy in response to levosimendan were increased. Finally, all protective effects were prevented by both mitoKATP channels inhibition and NOS blocking. In HSC, levosimendan was able to modulate the oxidative balance and inhibit autophagy without improving cell viability and apoptosis. CONCLUSIONS:Levosimendan protects hepatocytes against oxidative injuries by autophagic-dependent inhibition of apoptosis and the activation of survival signalling. Such effects would involve mitoKATP channels opening and the modulation of NO release by the different NOS isoforms. In HSC, levosimendan would also play a role in cell activation and possible evolution toward fibrosis. These findings highlight the potential of levosimendan as a therapeutic agent for the treatment or prevention of liver ischemia/reperfusion injuries.http://europepmc.org/articles/PMC4400069?pdf=render |
| spellingShingle | Elena Grossini Kevin Bellofatto Serena Farruggio Lorenzo Sigaudo Patrizia Marotta Giulia Raina Veronica De Giuli David Mary Piero Pollesello Rosalba Minisini Mario Pirisi Giovanni Vacca Levosimendan inhibits peroxidation in hepatocytes by modulating apoptosis/autophagy interplay. PLoS ONE |
| title | Levosimendan inhibits peroxidation in hepatocytes by modulating apoptosis/autophagy interplay. |
| title_full | Levosimendan inhibits peroxidation in hepatocytes by modulating apoptosis/autophagy interplay. |
| title_fullStr | Levosimendan inhibits peroxidation in hepatocytes by modulating apoptosis/autophagy interplay. |
| title_full_unstemmed | Levosimendan inhibits peroxidation in hepatocytes by modulating apoptosis/autophagy interplay. |
| title_short | Levosimendan inhibits peroxidation in hepatocytes by modulating apoptosis/autophagy interplay. |
| title_sort | levosimendan inhibits peroxidation in hepatocytes by modulating apoptosis autophagy interplay |
| url | http://europepmc.org/articles/PMC4400069?pdf=render |
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