Levosimendan inhibits peroxidation in hepatocytes by modulating apoptosis/autophagy interplay
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...
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| Veröffentlicht in: | PloS one 2015-04, Vol.10 (4), p.e0124742-e0124742 |
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| creator | Grossini, Elena Bellofatto, Kevin Farruggio, Serena Sigaudo, Lorenzo Marotta, Patrizia Raina, Giulia De Giuli, Veronica Mary, David Pollesello, Piero Minisini, Rosalba Pirisi, Mario Vacca, Giovanni |
| description | 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.
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.
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. |
| doi_str_mv | 10.1371/journal.pone.0124742 |
| format | Article |
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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.
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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0124742</identifier><identifier>PMID: 25880552</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Anti-Arrhythmia Agents - pharmacology ; Apoptosis ; Apoptosis - drug effects ; Autophagy - drug effects ; Blotting, Western ; Cell activation ; Cell death ; Cell survival ; Channels ; Chemical compounds ; Fibrosis ; Hepatocytes ; Hepatocytes - cytology ; Hepatocytes - drug effects ; Human performance ; Humans ; Hydrazones - pharmacology ; Inhibition ; Injuries ; Injury prevention ; Ischemia ; Isoforms ; Lipid Peroxidation - drug effects ; Liver ; Male ; Membrane permeability ; Membrane potential ; Mitochondrial Membrane Transport Proteins - drug effects ; Mitochondrial permeability transition pore ; MPTP ; Nitric oxide ; Nitric Oxide - metabolism ; Nitric Oxide Synthase Type II - metabolism ; Nitric-oxide synthase ; Oxidative stress ; Oxidative Stress - drug effects ; Permeability ; Peroxidation ; Phagocytosis ; Pharmacology ; Potassium Channels - metabolism ; Pretreatment ; Pyridazines - pharmacology ; Rats ; Rats, Sprague-Dawley ; Reperfusion ; Signaling ; Simendan ; Stellate cells ; Survival</subject><ispartof>PloS one, 2015-04, Vol.10 (4), p.e0124742-e0124742</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Grossini et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Grossini et al 2015 Grossini et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-3230c80f448a6e12857e622413971fd35556bbb1bed8b66f0b7d1f54b6f4a2d23</citedby><cites>FETCH-LOGICAL-c692t-3230c80f448a6e12857e622413971fd35556bbb1bed8b66f0b7d1f54b6f4a2d23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4400069/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4400069/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25880552$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Safadi, Rifaat</contributor><creatorcontrib>Grossini, Elena</creatorcontrib><creatorcontrib>Bellofatto, Kevin</creatorcontrib><creatorcontrib>Farruggio, Serena</creatorcontrib><creatorcontrib>Sigaudo, Lorenzo</creatorcontrib><creatorcontrib>Marotta, Patrizia</creatorcontrib><creatorcontrib>Raina, Giulia</creatorcontrib><creatorcontrib>De Giuli, Veronica</creatorcontrib><creatorcontrib>Mary, David</creatorcontrib><creatorcontrib>Pollesello, Piero</creatorcontrib><creatorcontrib>Minisini, Rosalba</creatorcontrib><creatorcontrib>Pirisi, Mario</creatorcontrib><creatorcontrib>Vacca, Giovanni</creatorcontrib><title>Levosimendan inhibits peroxidation in hepatocytes by modulating apoptosis/autophagy interplay</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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.
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.
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.</description><subject>Animals</subject><subject>Anti-Arrhythmia Agents - pharmacology</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Autophagy - drug effects</subject><subject>Blotting, Western</subject><subject>Cell activation</subject><subject>Cell death</subject><subject>Cell survival</subject><subject>Channels</subject><subject>Chemical compounds</subject><subject>Fibrosis</subject><subject>Hepatocytes</subject><subject>Hepatocytes - cytology</subject><subject>Hepatocytes - drug effects</subject><subject>Human performance</subject><subject>Humans</subject><subject>Hydrazones - pharmacology</subject><subject>Inhibition</subject><subject>Injuries</subject><subject>Injury prevention</subject><subject>Ischemia</subject><subject>Isoforms</subject><subject>Lipid Peroxidation - drug effects</subject><subject>Liver</subject><subject>Male</subject><subject>Membrane permeability</subject><subject>Membrane potential</subject><subject>Mitochondrial Membrane Transport Proteins - drug effects</subject><subject>Mitochondrial permeability transition pore</subject><subject>MPTP</subject><subject>Nitric oxide</subject><subject>Nitric Oxide - metabolism</subject><subject>Nitric Oxide Synthase Type II - metabolism</subject><subject>Nitric-oxide synthase</subject><subject>Oxidative stress</subject><subject>Oxidative Stress - drug effects</subject><subject>Permeability</subject><subject>Peroxidation</subject><subject>Phagocytosis</subject><subject>Pharmacology</subject><subject>Potassium Channels - metabolism</subject><subject>Pretreatment</subject><subject>Pyridazines - pharmacology</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Reperfusion</subject><subject>Signaling</subject><subject>Simendan</subject><subject>Stellate cells</subject><subject>Survival</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk9tq3DAQhk1padK0b1BaQ6G0F7vR2fJNIYQeFhYCPd0VIdmyrcW2HEkO2bevnHXCuuSi-MJm9P3_jMYzSfIagjXEGTzf2dH1sl0PttdrABHJCHqSnMIcoxVDAD89-j5JXni_A4Biztjz5ARRzgGl6DT5s9U31ptO96XsU9M3Rpng00E7e2tKGYydommjBxlssQ_ap2qfdrYc23jY16kc7BCigz-XY7BDI-t9FATthlbuXybPKtl6_Wp-nyW_vnz-eflttb36urm82K4KlqOwwgiDgoOKEC6ZhojTTDOECMR5BqsSU0qZUgoqXXLFWAVUVsKKEsUqIlGJ8Fny9uA7tNaLuTNeQJZhjgjiMBKbA1FauRODM510e2GlEXcB62ohXTBFqwUFOs81ZVjRnJS55BnhGGJCpcIo1ha9Ps3ZRtXpstB9cLJdmC5PetOI2t4IQgAALI8GH2YDZ69H7YPojC9028pe2_GubsI4x3iq-90_6OO3m6laxguYvrIxbzGZiguCKM4By6a060eo-JS6M0Uco8rE-ELwcSGITNC3oZaj92Lz4_v_s1e_l-z7I7bRsg2Nt-04TZtfguQAFs5673T10GQIxLQF990Q0xaIeQui7M3xD3oQ3Y89_gvqSwJ3</recordid><startdate>20150416</startdate><enddate>20150416</enddate><creator>Grossini, Elena</creator><creator>Bellofatto, Kevin</creator><creator>Farruggio, Serena</creator><creator>Sigaudo, Lorenzo</creator><creator>Marotta, Patrizia</creator><creator>Raina, Giulia</creator><creator>De Giuli, Veronica</creator><creator>Mary, David</creator><creator>Pollesello, Piero</creator><creator>Minisini, Rosalba</creator><creator>Pirisi, Mario</creator><creator>Vacca, Giovanni</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150416</creationdate><title>Levosimendan inhibits peroxidation in hepatocytes by modulating apoptosis/autophagy interplay</title><author>Grossini, Elena ; Bellofatto, Kevin ; Farruggio, Serena ; Sigaudo, Lorenzo ; Marotta, Patrizia ; Raina, Giulia ; De Giuli, Veronica ; Mary, David ; Pollesello, Piero ; Minisini, Rosalba ; Pirisi, Mario ; Vacca, Giovanni</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-3230c80f448a6e12857e622413971fd35556bbb1bed8b66f0b7d1f54b6f4a2d23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Animals</topic><topic>Anti-Arrhythmia Agents - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Grossini, Elena</au><au>Bellofatto, Kevin</au><au>Farruggio, Serena</au><au>Sigaudo, Lorenzo</au><au>Marotta, Patrizia</au><au>Raina, Giulia</au><au>De Giuli, Veronica</au><au>Mary, David</au><au>Pollesello, Piero</au><au>Minisini, Rosalba</au><au>Pirisi, Mario</au><au>Vacca, Giovanni</au><au>Safadi, Rifaat</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Levosimendan inhibits peroxidation in hepatocytes by modulating apoptosis/autophagy interplay</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-04-16</date><risdate>2015</risdate><volume>10</volume><issue>4</issue><spage>e0124742</spage><epage>e0124742</epage><pages>e0124742-e0124742</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>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.
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.
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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25880552</pmid><doi>10.1371/journal.pone.0124742</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2015-04, Vol.10 (4), p.e0124742-e0124742 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1673824281 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Animals Anti-Arrhythmia Agents - pharmacology Apoptosis Apoptosis - drug effects Autophagy - drug effects Blotting, Western Cell activation Cell death Cell survival Channels Chemical compounds Fibrosis Hepatocytes Hepatocytes - cytology Hepatocytes - drug effects Human performance Humans Hydrazones - pharmacology Inhibition Injuries Injury prevention Ischemia Isoforms Lipid Peroxidation - drug effects Liver Male Membrane permeability Membrane potential Mitochondrial Membrane Transport Proteins - drug effects Mitochondrial permeability transition pore MPTP Nitric oxide Nitric Oxide - metabolism Nitric Oxide Synthase Type II - metabolism Nitric-oxide synthase Oxidative stress Oxidative Stress - drug effects Permeability Peroxidation Phagocytosis Pharmacology Potassium Channels - metabolism Pretreatment Pyridazines - pharmacology Rats Rats, Sprague-Dawley Reperfusion Signaling Simendan Stellate cells Survival |
| title | Levosimendan inhibits peroxidation in hepatocytes by modulating apoptosis/autophagy interplay |
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