Modulation of myocardial mitochondrial mechanisms during severe polymicrobial sepsis in the rat
We tested the hypothesis that 5-Hydroxydecanoic acid (5HD), a putative mitoK(ATP) channel blocker, will reverse sepsis-induced cardiodynamic and adult rat ventricular myocyte (ARVM) contractile dysfunction, restore mitochondrial membrane permeability alterations and improve survival. Male Sprague-Da...
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| Veröffentlicht in: | PloS one 2011-06, Vol.6 (6), p.e21285-e21285 |
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| creator | Chopra, Mani Golden, Honey B Mullapudi, Srinivas Dowhan, William Dostal, David E Sharma, Avadhesh C |
| description | We tested the hypothesis that 5-Hydroxydecanoic acid (5HD), a putative mitoK(ATP) channel blocker, will reverse sepsis-induced cardiodynamic and adult rat ventricular myocyte (ARVM) contractile dysfunction, restore mitochondrial membrane permeability alterations and improve survival.
Male Sprague-Dawley rats (350-400 g) were made septic using 400 mg/kg cecal inoculum, ip. Sham animals received 5% dextrose water, ip. The Voltage Dependent Anion Channels (VDAC1), Bax and cytochrome C levels were determined in isolated single ARVMs obtained from sham and septic rat heart. Mitochondria and cytosolic fractions were isolated from ARVMs treated with norepinephrine (NE, 10 µmoles) in the presence/absence of 5HD (100 µmoles). A continuous infusion of 5HD using an Alzet pump reversed sepsis-induced mortality when administered at the time of induction of sepsis (-40%) and at 6 hr post-sepsis (-20%). Electrocardiography revealed that 5HD reversed sepsis-induced decrease in the average ejection fraction, Simpsons+m Mode (53.5±2.5 in sepsis and 69.2±1.2 at 24 hr in sepsis+5HD vs. 79.9±1.5 basal group) and cardiac output (63.3±1.2 mL/min sepsis and 79.3±3.9 mL/min at 24 hr in sepsis+5HD vs. 85.8±1.5 mL/min basal group). The treatment of ARVMs with 5HD also reversed sepsis-induced depressed contractility in both the vehicle and NE-treated groups. Sepsis produced a significant downregulation of VDAC1, and upregulation of Bax levels, along with mitochondrial membrane potential collapse in ARVMs. Pretreatment of septic ARVMs with 5HD blocked a NE-induced decrease in the VDAC1 and release of cytochrome C.
The data suggest that Bax activation is an upstream event that may precede the opening of the mitoK(ATP) channels in sepsis. We concluded that mitoK(ATP) channel inhibition via decreased mitochondrial membrane potential and reduced release of cytochrome C provided protection against sepsis-induced ARVM and myocardial contractile dysfunction. |
| doi_str_mv | 10.1371/journal.pone.0021285 |
| format | Article |
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Male Sprague-Dawley rats (350-400 g) were made septic using 400 mg/kg cecal inoculum, ip. Sham animals received 5% dextrose water, ip. The Voltage Dependent Anion Channels (VDAC1), Bax and cytochrome C levels were determined in isolated single ARVMs obtained from sham and septic rat heart. Mitochondria and cytosolic fractions were isolated from ARVMs treated with norepinephrine (NE, 10 µmoles) in the presence/absence of 5HD (100 µmoles). A continuous infusion of 5HD using an Alzet pump reversed sepsis-induced mortality when administered at the time of induction of sepsis (-40%) and at 6 hr post-sepsis (-20%). Electrocardiography revealed that 5HD reversed sepsis-induced decrease in the average ejection fraction, Simpsons+m Mode (53.5±2.5 in sepsis and 69.2±1.2 at 24 hr in sepsis+5HD vs. 79.9±1.5 basal group) and cardiac output (63.3±1.2 mL/min sepsis and 79.3±3.9 mL/min at 24 hr in sepsis+5HD vs. 85.8±1.5 mL/min basal group). The treatment of ARVMs with 5HD also reversed sepsis-induced depressed contractility in both the vehicle and NE-treated groups. Sepsis produced a significant downregulation of VDAC1, and upregulation of Bax levels, along with mitochondrial membrane potential collapse in ARVMs. Pretreatment of septic ARVMs with 5HD blocked a NE-induced decrease in the VDAC1 and release of cytochrome C.
The data suggest that Bax activation is an upstream event that may precede the opening of the mitoK(ATP) channels in sepsis. We concluded that mitoK(ATP) channel inhibition via decreased mitochondrial membrane potential and reduced release of cytochrome C provided protection against sepsis-induced ARVM and myocardial contractile dysfunction.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0021285</identifier><identifier>PMID: 21712982</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Anion channels ; Anti-Arrhythmia Agents - pharmacology ; Apoptosis ; Bax protein ; bcl-2-Associated X Protein - metabolism ; Biochemistry ; Biology ; Body Temperature - drug effects ; Cardiac output ; Cardiology ; Cecum ; Channels ; Contractility ; Cytochrome ; Cytochrome c ; Cytochromes c - metabolism ; Decanoic Acids - metabolism ; Decanoic Acids - pharmacology ; Dentistry ; Dextrose ; EKG ; Electrocardiography ; Heart ; Heart diseases ; Hemodynamics ; High definition television ; Hydroxy Acids - metabolism ; Hydroxy Acids - pharmacology ; Infection ; Infusion ; Inoculum ; Kinases ; Laboratories ; Male ; Medicine ; Membrane permeability ; Membrane potential ; Membrane Potential, Mitochondrial - drug effects ; Mitochondria ; Mitochondria - drug effects ; Mitochondria - metabolism ; Mitochondria - ultrastructure ; Molecular biology ; Mortality ; Muscle contraction ; Myocardial Contraction - drug effects ; Myocardium - cytology ; Myocardium - metabolism ; Myocytes, Cardiac - cytology ; Myocytes, Cardiac - drug effects ; Myocytes, Cardiac - metabolism ; Norepinephrine ; Permeability ; Potassium Channel Blockers - metabolism ; Potassium Channel Blockers - pharmacology ; Potassium Channels - metabolism ; Pretreatment ; Proteins ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Rodents ; Science ; Sepsis ; Sepsis - microbiology ; Sepsis - mortality ; Sepsis - physiopathology ; Tumor Necrosis Factor-alpha - metabolism ; Ultrasonic imaging ; Ventricle ; Voltage-Dependent Anion Channel 1 - metabolism</subject><ispartof>PloS one, 2011-06, Vol.6 (6), p.e21285-e21285</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Chopra et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://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>Chopra et al. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c691t-8b9064c5c29dc2ca8b752b600d6515072dee8fcddf0e719b1dc5e8e684dcaaaf3</citedby><cites>FETCH-LOGICAL-c691t-8b9064c5c29dc2ca8b752b600d6515072dee8fcddf0e719b1dc5e8e684dcaaaf3</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/PMC3119671/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3119671/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21712982$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chopra, Mani</creatorcontrib><creatorcontrib>Golden, Honey B</creatorcontrib><creatorcontrib>Mullapudi, Srinivas</creatorcontrib><creatorcontrib>Dowhan, William</creatorcontrib><creatorcontrib>Dostal, David E</creatorcontrib><creatorcontrib>Sharma, Avadhesh C</creatorcontrib><title>Modulation of myocardial mitochondrial mechanisms during severe polymicrobial sepsis in the rat</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>We tested the hypothesis that 5-Hydroxydecanoic acid (5HD), a putative mitoK(ATP) channel blocker, will reverse sepsis-induced cardiodynamic and adult rat ventricular myocyte (ARVM) contractile dysfunction, restore mitochondrial membrane permeability alterations and improve survival.
Male Sprague-Dawley rats (350-400 g) were made septic using 400 mg/kg cecal inoculum, ip. Sham animals received 5% dextrose water, ip. The Voltage Dependent Anion Channels (VDAC1), Bax and cytochrome C levels were determined in isolated single ARVMs obtained from sham and septic rat heart. Mitochondria and cytosolic fractions were isolated from ARVMs treated with norepinephrine (NE, 10 µmoles) in the presence/absence of 5HD (100 µmoles). A continuous infusion of 5HD using an Alzet pump reversed sepsis-induced mortality when administered at the time of induction of sepsis (-40%) and at 6 hr post-sepsis (-20%). Electrocardiography revealed that 5HD reversed sepsis-induced decrease in the average ejection fraction, Simpsons+m Mode (53.5±2.5 in sepsis and 69.2±1.2 at 24 hr in sepsis+5HD vs. 79.9±1.5 basal group) and cardiac output (63.3±1.2 mL/min sepsis and 79.3±3.9 mL/min at 24 hr in sepsis+5HD vs. 85.8±1.5 mL/min basal group). The treatment of ARVMs with 5HD also reversed sepsis-induced depressed contractility in both the vehicle and NE-treated groups. Sepsis produced a significant downregulation of VDAC1, and upregulation of Bax levels, along with mitochondrial membrane potential collapse in ARVMs. Pretreatment of septic ARVMs with 5HD blocked a NE-induced decrease in the VDAC1 and release of cytochrome C.
The data suggest that Bax activation is an upstream event that may precede the opening of the mitoK(ATP) channels in sepsis. We concluded that mitoK(ATP) channel inhibition via decreased mitochondrial membrane potential and reduced release of cytochrome C provided protection against sepsis-induced ARVM and myocardial contractile dysfunction.</description><subject>Animals</subject><subject>Anion channels</subject><subject>Anti-Arrhythmia Agents - pharmacology</subject><subject>Apoptosis</subject><subject>Bax protein</subject><subject>bcl-2-Associated X Protein - metabolism</subject><subject>Biochemistry</subject><subject>Biology</subject><subject>Body Temperature - drug effects</subject><subject>Cardiac output</subject><subject>Cardiology</subject><subject>Cecum</subject><subject>Channels</subject><subject>Contractility</subject><subject>Cytochrome</subject><subject>Cytochrome c</subject><subject>Cytochromes c - metabolism</subject><subject>Decanoic Acids - metabolism</subject><subject>Decanoic Acids - pharmacology</subject><subject>Dentistry</subject><subject>Dextrose</subject><subject>EKG</subject><subject>Electrocardiography</subject><subject>Heart</subject><subject>Heart diseases</subject><subject>Hemodynamics</subject><subject>High definition television</subject><subject>Hydroxy Acids - metabolism</subject><subject>Hydroxy Acids - pharmacology</subject><subject>Infection</subject><subject>Infusion</subject><subject>Inoculum</subject><subject>Kinases</subject><subject>Laboratories</subject><subject>Male</subject><subject>Medicine</subject><subject>Membrane permeability</subject><subject>Membrane potential</subject><subject>Membrane Potential, Mitochondrial - drug effects</subject><subject>Mitochondria</subject><subject>Mitochondria - drug effects</subject><subject>Mitochondria - metabolism</subject><subject>Mitochondria - ultrastructure</subject><subject>Molecular biology</subject><subject>Mortality</subject><subject>Muscle contraction</subject><subject>Myocardial Contraction - drug effects</subject><subject>Myocardium - cytology</subject><subject>Myocardium - metabolism</subject><subject>Myocytes, Cardiac - cytology</subject><subject>Myocytes, Cardiac - drug effects</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>Norepinephrine</subject><subject>Permeability</subject><subject>Potassium Channel Blockers - 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Academic</collection><collection>ProQuest Engineering Collection</collection><collection>Biological Sciences</collection><collection>Agriculture Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest advanced technologies & aerospace journals</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - 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>Chopra, Mani</au><au>Golden, Honey B</au><au>Mullapudi, Srinivas</au><au>Dowhan, William</au><au>Dostal, David E</au><au>Sharma, Avadhesh C</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Modulation of myocardial mitochondrial mechanisms during severe polymicrobial sepsis in the rat</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2011-06-21</date><risdate>2011</risdate><volume>6</volume><issue>6</issue><spage>e21285</spage><epage>e21285</epage><pages>e21285-e21285</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>We tested the hypothesis that 5-Hydroxydecanoic acid (5HD), a putative mitoK(ATP) channel blocker, will reverse sepsis-induced cardiodynamic and adult rat ventricular myocyte (ARVM) contractile dysfunction, restore mitochondrial membrane permeability alterations and improve survival.
Male Sprague-Dawley rats (350-400 g) were made septic using 400 mg/kg cecal inoculum, ip. Sham animals received 5% dextrose water, ip. The Voltage Dependent Anion Channels (VDAC1), Bax and cytochrome C levels were determined in isolated single ARVMs obtained from sham and septic rat heart. Mitochondria and cytosolic fractions were isolated from ARVMs treated with norepinephrine (NE, 10 µmoles) in the presence/absence of 5HD (100 µmoles). A continuous infusion of 5HD using an Alzet pump reversed sepsis-induced mortality when administered at the time of induction of sepsis (-40%) and at 6 hr post-sepsis (-20%). Electrocardiography revealed that 5HD reversed sepsis-induced decrease in the average ejection fraction, Simpsons+m Mode (53.5±2.5 in sepsis and 69.2±1.2 at 24 hr in sepsis+5HD vs. 79.9±1.5 basal group) and cardiac output (63.3±1.2 mL/min sepsis and 79.3±3.9 mL/min at 24 hr in sepsis+5HD vs. 85.8±1.5 mL/min basal group). The treatment of ARVMs with 5HD also reversed sepsis-induced depressed contractility in both the vehicle and NE-treated groups. Sepsis produced a significant downregulation of VDAC1, and upregulation of Bax levels, along with mitochondrial membrane potential collapse in ARVMs. Pretreatment of septic ARVMs with 5HD blocked a NE-induced decrease in the VDAC1 and release of cytochrome C.
The data suggest that Bax activation is an upstream event that may precede the opening of the mitoK(ATP) channels in sepsis. We concluded that mitoK(ATP) channel inhibition via decreased mitochondrial membrane potential and reduced release of cytochrome C provided protection against sepsis-induced ARVM and myocardial contractile dysfunction.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21712982</pmid><doi>10.1371/journal.pone.0021285</doi><tpages>e21285</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2011-06, Vol.6 (6), p.e21285-e21285 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1304811205 |
| source | PubMed (Medline); MEDLINE; Public Library of Science; DOAJ Directory of Open Access Journals; Free Full-Text Journals in Chemistry; EZB Electronic Journals Library |
| subjects | Animals Anion channels Anti-Arrhythmia Agents - pharmacology Apoptosis Bax protein bcl-2-Associated X Protein - metabolism Biochemistry Biology Body Temperature - drug effects Cardiac output Cardiology Cecum Channels Contractility Cytochrome Cytochrome c Cytochromes c - metabolism Decanoic Acids - metabolism Decanoic Acids - pharmacology Dentistry Dextrose EKG Electrocardiography Heart Heart diseases Hemodynamics High definition television Hydroxy Acids - metabolism Hydroxy Acids - pharmacology Infection Infusion Inoculum Kinases Laboratories Male Medicine Membrane permeability Membrane potential Membrane Potential, Mitochondrial - drug effects Mitochondria Mitochondria - drug effects Mitochondria - metabolism Mitochondria - ultrastructure Molecular biology Mortality Muscle contraction Myocardial Contraction - drug effects Myocardium - cytology Myocardium - metabolism Myocytes, Cardiac - cytology Myocytes, Cardiac - drug effects Myocytes, Cardiac - metabolism Norepinephrine Permeability Potassium Channel Blockers - metabolism Potassium Channel Blockers - pharmacology Potassium Channels - metabolism Pretreatment Proteins Random Allocation Rats Rats, Sprague-Dawley Rodents Science Sepsis Sepsis - microbiology Sepsis - mortality Sepsis - physiopathology Tumor Necrosis Factor-alpha - metabolism Ultrasonic imaging Ventricle Voltage-Dependent Anion Channel 1 - metabolism |
| title | Modulation of myocardial mitochondrial mechanisms during severe polymicrobial sepsis in the rat |
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