Levosimendan protects human hepatocytes from ischemia-reperfusion injury
Ischemia-reperfusion injury (IRI) is a major challenge in liver transplantation. The mitochondrial pathway plays a pivotal role in hepatic IRI. Levosimendan, a calcium channel sensitizer, was shown to attenuate apoptosis after IRI in animal livers. The aim of this study was to investigate the effect...
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| creator | Brunner, Stefanie N Bogert, Nicolai V Schnitzbauer, Andreas A Juengel, Eva Moritz, Anton Werner, Isabella Kornberger, Angela Beiras-Fernandez, Andres |
| description | Ischemia-reperfusion injury (IRI) is a major challenge in liver transplantation. The mitochondrial pathway plays a pivotal role in hepatic IRI. Levosimendan, a calcium channel sensitizer, was shown to attenuate apoptosis after IRI in animal livers. The aim of this study was to investigate the effect of levosimendan on apoptosis in human hepatocytes.
Primary human hepatocytes were either exposed to hypoxia or cultured under normoxic conditions. After the hypoxic phase, reoxygenation was implemented and cells were treated with different concentrations of levosimendan (10ng/ml, 100ng/ml, 1000ng/ml). The overall metabolic activity of the cells was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and aspartate aminotransferase (AST) levels were determined in order to quantify hepatic injury. Fluorescence-activated cell sorting (FACS) analysis was applied to measure necrosis and apoptosis. Finally, Western blotting was performed to analyze apoptotic pathway proteins.
Administration of levosimendan during reperfusion increases the metabolic activity of human hepatocytes and decreases AST levels. Moreover, apoptosis after IRI is reduced in treated vs. untreated hepatocytes, and levosimendan prevents down-regulation of the anti-apoptotic protein Bcl-2 as well as up-regulation of the pro-apoptotic protein BAX.
The present study suggests a protective effect of levosimendan on human hepatocytes. Our findings suggest that treatment with levosimendan during reperfusion attenuates apoptosis of human hepatocytes by influencing BAX and Bcl-2 levels. |
| doi_str_mv | 10.1371/journal.pone.0187839 |
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Primary human hepatocytes were either exposed to hypoxia or cultured under normoxic conditions. After the hypoxic phase, reoxygenation was implemented and cells were treated with different concentrations of levosimendan (10ng/ml, 100ng/ml, 1000ng/ml). The overall metabolic activity of the cells was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and aspartate aminotransferase (AST) levels were determined in order to quantify hepatic injury. Fluorescence-activated cell sorting (FACS) analysis was applied to measure necrosis and apoptosis. Finally, Western blotting was performed to analyze apoptotic pathway proteins.
Administration of levosimendan during reperfusion increases the metabolic activity of human hepatocytes and decreases AST levels. Moreover, apoptosis after IRI is reduced in treated vs. untreated hepatocytes, and levosimendan prevents down-regulation of the anti-apoptotic protein Bcl-2 as well as up-regulation of the pro-apoptotic protein BAX.
The present study suggests a protective effect of levosimendan on human hepatocytes. Our findings suggest that treatment with levosimendan during reperfusion attenuates apoptosis of human hepatocytes by influencing BAX and Bcl-2 levels.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0187839</identifier><identifier>PMID: 29145424</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adenosine ; Analysis ; Apoptosis ; Aspartate aminotransferase ; BAX protein ; Bcl-2 protein ; Biology and Life Sciences ; Bromine compounds ; Calcium ; Cardiology ; Complications and side effects ; Cytochrome ; Cytokines ; Drug therapy ; Flow cytometry ; Fluorescence ; Heart failure ; Heart surgery ; Hepatocytes ; Hepatology ; Hypoxia ; Injuries ; Injury analysis ; Ischemia ; Liver ; Liver transplantation ; Liver transplants ; Medicine and Health Sciences ; Metabolism ; Mitochondria ; Physiological aspects ; Physiology ; Potassium ; Proteins ; Reperfusion ; Reperfusion injury ; Research and analysis methods ; Rodents ; Transplantation ; Western blotting</subject><ispartof>PloS one, 2017-11, Vol.12 (11), p.e0187839-e0187839</ispartof><rights>COPYRIGHT 2017 Public Library of Science</rights><rights>2017 Brunner 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>2017 Brunner et al 2017 Brunner et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c585t-52f1d89e9374021494c9a0d64a85ccda80b495dd11aaed3edd2f2dc49114a5103</citedby><cites>FETCH-LOGICAL-c585t-52f1d89e9374021494c9a0d64a85ccda80b495dd11aaed3edd2f2dc49114a5103</cites><orcidid>0000-0003-4932-1924</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5690693/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5690693/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79569,79570</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29145424$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Brunner, Stefanie N</creatorcontrib><creatorcontrib>Bogert, Nicolai V</creatorcontrib><creatorcontrib>Schnitzbauer, Andreas A</creatorcontrib><creatorcontrib>Juengel, Eva</creatorcontrib><creatorcontrib>Moritz, Anton</creatorcontrib><creatorcontrib>Werner, Isabella</creatorcontrib><creatorcontrib>Kornberger, Angela</creatorcontrib><creatorcontrib>Beiras-Fernandez, Andres</creatorcontrib><title>Levosimendan protects human hepatocytes from ischemia-reperfusion injury</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Ischemia-reperfusion injury (IRI) is a major challenge in liver transplantation. The mitochondrial pathway plays a pivotal role in hepatic IRI. Levosimendan, a calcium channel sensitizer, was shown to attenuate apoptosis after IRI in animal livers. The aim of this study was to investigate the effect of levosimendan on apoptosis in human hepatocytes.
Primary human hepatocytes were either exposed to hypoxia or cultured under normoxic conditions. After the hypoxic phase, reoxygenation was implemented and cells were treated with different concentrations of levosimendan (10ng/ml, 100ng/ml, 1000ng/ml). The overall metabolic activity of the cells was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and aspartate aminotransferase (AST) levels were determined in order to quantify hepatic injury. Fluorescence-activated cell sorting (FACS) analysis was applied to measure necrosis and apoptosis. Finally, Western blotting was performed to analyze apoptotic pathway proteins.
Administration of levosimendan during reperfusion increases the metabolic activity of human hepatocytes and decreases AST levels. Moreover, apoptosis after IRI is reduced in treated vs. untreated hepatocytes, and levosimendan prevents down-regulation of the anti-apoptotic protein Bcl-2 as well as up-regulation of the pro-apoptotic protein BAX.
The present study suggests a protective effect of levosimendan on human hepatocytes. Our findings suggest that treatment with levosimendan during reperfusion attenuates apoptosis of human hepatocytes by influencing BAX and Bcl-2 levels.</description><subject>Adenosine</subject><subject>Analysis</subject><subject>Apoptosis</subject><subject>Aspartate aminotransferase</subject><subject>BAX protein</subject><subject>Bcl-2 protein</subject><subject>Biology and Life Sciences</subject><subject>Bromine compounds</subject><subject>Calcium</subject><subject>Cardiology</subject><subject>Complications and side effects</subject><subject>Cytochrome</subject><subject>Cytokines</subject><subject>Drug therapy</subject><subject>Flow cytometry</subject><subject>Fluorescence</subject><subject>Heart failure</subject><subject>Heart surgery</subject><subject>Hepatocytes</subject><subject>Hepatology</subject><subject>Hypoxia</subject><subject>Injuries</subject><subject>Injury analysis</subject><subject>Ischemia</subject><subject>Liver</subject><subject>Liver 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Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Brunner, Stefanie N</au><au>Bogert, Nicolai V</au><au>Schnitzbauer, Andreas A</au><au>Juengel, Eva</au><au>Moritz, Anton</au><au>Werner, Isabella</au><au>Kornberger, Angela</au><au>Beiras-Fernandez, Andres</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Levosimendan protects human hepatocytes from ischemia-reperfusion injury</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2017-11-16</date><risdate>2017</risdate><volume>12</volume><issue>11</issue><spage>e0187839</spage><epage>e0187839</epage><pages>e0187839-e0187839</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Ischemia-reperfusion injury (IRI) is a major challenge in liver transplantation. The mitochondrial pathway plays a pivotal role in hepatic IRI. Levosimendan, a calcium channel sensitizer, was shown to attenuate apoptosis after IRI in animal livers. The aim of this study was to investigate the effect of levosimendan on apoptosis in human hepatocytes.
Primary human hepatocytes were either exposed to hypoxia or cultured under normoxic conditions. After the hypoxic phase, reoxygenation was implemented and cells were treated with different concentrations of levosimendan (10ng/ml, 100ng/ml, 1000ng/ml). The overall metabolic activity of the cells was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and aspartate aminotransferase (AST) levels were determined in order to quantify hepatic injury. Fluorescence-activated cell sorting (FACS) analysis was applied to measure necrosis and apoptosis. Finally, Western blotting was performed to analyze apoptotic pathway proteins.
Administration of levosimendan during reperfusion increases the metabolic activity of human hepatocytes and decreases AST levels. Moreover, apoptosis after IRI is reduced in treated vs. untreated hepatocytes, and levosimendan prevents down-regulation of the anti-apoptotic protein Bcl-2 as well as up-regulation of the pro-apoptotic protein BAX.
The present study suggests a protective effect of levosimendan on human hepatocytes. Our findings suggest that treatment with levosimendan during reperfusion attenuates apoptosis of human hepatocytes by influencing BAX and Bcl-2 levels.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>29145424</pmid><doi>10.1371/journal.pone.0187839</doi><orcidid>https://orcid.org/0000-0003-4932-1924</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Adenosine Analysis Apoptosis Aspartate aminotransferase BAX protein Bcl-2 protein Biology and Life Sciences Bromine compounds Calcium Cardiology Complications and side effects Cytochrome Cytokines Drug therapy Flow cytometry Fluorescence Heart failure Heart surgery Hepatocytes Hepatology Hypoxia Injuries Injury analysis Ischemia Liver Liver transplantation Liver transplants Medicine and Health Sciences Metabolism Mitochondria Physiological aspects Physiology Potassium Proteins Reperfusion Reperfusion injury Research and analysis methods Rodents Transplantation Western blotting |
| title | Levosimendan protects human hepatocytes from ischemia-reperfusion injury |
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