Wnt/β-Catenin Antagonist Pyrvinium Exerts Cardioprotective Effects in Polymicrobial Sepsis Model by Attenuating Calcium Dyshomeostasis and Mitochondrial Dysfunction
Calcium dysregulation and mitochondrial dysfunction are key elements in the development of sepsis-induced cardiac dysfunction. Evidences have suggested that inhibition of Wnt/β-Catenin signalling prevents cardiac dysfunction and remodelling in surgical, hypertension and pressure overload models. The...
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| Veröffentlicht in: | Cardiovascular toxicology 2021-07, Vol.21 (7), p.517-532 |
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| creator | Sen, Pallavi Gupta, Kirti Kumari, Abha Singh, Gaaminepreet Pandey, Sneha Singh, Ragini |
| description | Calcium dysregulation and mitochondrial dysfunction are key elements in the development of sepsis-induced cardiac dysfunction. Evidences have suggested that inhibition of Wnt/β-Catenin signalling prevents cardiac dysfunction and remodelling in surgical, hypertension and pressure overload models. The present study investigated the effects of Wnt/β-Catenin inhibitor on calcium overload and mitochondrial dysfunction in rat sepsis model of cardiomyopathy. Induction of sepsis by cecal ligation puncture (CLP) resulted in the up-regulation of cardiac β-catenin transcriptional levels and cardiac dysfunction depicted by increased serum lactate dehydrogenase, CK-MB levels reduced maximum (d
p
/d
t
max.) and minimum developed pressure (d
p
/d
t
min.), increased LVEsDP and relaxation constant tau values. Moreover, oxidative and inflammatory stress, immune cell infiltration, increased myeloperoxidase activity, enhanced caspase-3 activity and fibronectin protein levels were observed in septic rat’s heart. Also, septic rat’s heart displayed mitochondrial dysfunction due to mPTP opening, increased calcium up-regulation in left ventricular apex tissues and whole heart, increased collagen staining, necrosis and structural damage. Pre-treatment with Wnt/β-Catenin antagonist attenuated sepsis-induced serum and tissue biochemical changes, cardiac dysfunction and structural alterations by inhibiting mitochondrial mPTP opening and restricting calcium overloading in cardiac tissue. |
| doi_str_mv | 10.1007/s12012-021-09643-4 |
| format | Article |
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p
/d
t
max.) and minimum developed pressure (d
p
/d
t
min.), increased LVEsDP and relaxation constant tau values. Moreover, oxidative and inflammatory stress, immune cell infiltration, increased myeloperoxidase activity, enhanced caspase-3 activity and fibronectin protein levels were observed in septic rat’s heart. Also, septic rat’s heart displayed mitochondrial dysfunction due to mPTP opening, increased calcium up-regulation in left ventricular apex tissues and whole heart, increased collagen staining, necrosis and structural damage. Pre-treatment with Wnt/β-Catenin antagonist attenuated sepsis-induced serum and tissue biochemical changes, cardiac dysfunction and structural alterations by inhibiting mitochondrial mPTP opening and restricting calcium overloading in cardiac tissue.</description><identifier>ISSN: 1530-7905</identifier><identifier>EISSN: 1559-0259</identifier><identifier>DOI: 10.1007/s12012-021-09643-4</identifier><identifier>PMID: 33723718</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Animals ; beta Catenin - genetics ; beta Catenin - metabolism ; Biomedical and Life Sciences ; Biomedicine ; Calcium ; Calcium (mitochondrial) ; Calcium - metabolism ; Calcium homeostasis ; Cardiology ; Cardiomyopathies - etiology ; Cardiomyopathies - metabolism ; Cardiomyopathies - physiopathology ; Cardiomyopathies - prevention & control ; Cardiomyopathy ; Caspase-3 ; Cecum ; Coinfection - drug therapy ; Coinfection - metabolism ; Coinfection - microbiology ; Collagen ; Cytokines - metabolism ; Disease Models, Animal ; Fibronectin ; Fibrosis ; Gene regulation ; Heart diseases ; Hypertension ; Immune system ; Inflammation ; Inflammation Mediators - metabolism ; L-Lactate dehydrogenase ; Lactate dehydrogenase ; Lactic acid ; Male ; Mitochondria, Heart - drug effects ; Mitochondria, Heart - metabolism ; Mitochondria, Heart - pathology ; Mitochondrial permeability transition pore ; Mitochondrial Permeability Transition Pore - metabolism ; Myocytes, Cardiac - drug effects ; Myocytes, Cardiac - metabolism ; Myocytes, Cardiac - pathology ; Necrosis ; Overloading ; Oxidative Stress - drug effects ; Peroxidase ; Pharmacology/Toxicology ; Pyrvinium Compounds - pharmacology ; Rats ; Rats, Wistar ; Sepsis ; Sepsis - drug therapy ; Sepsis - metabolism ; Sepsis - microbiology ; Tissues ; Transcription ; Ventricle ; Ventricular Function, Left - drug effects ; Ventricular Pressure - drug effects ; Wnt protein ; Wnt Signaling Pathway - drug effects ; β-Catenin</subject><ispartof>Cardiovascular toxicology, 2021-07, Vol.21 (7), p.517-532</ispartof><rights>The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021</rights><rights>The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c375t-ba77a7860ae354f2c3f89010c9a5e9f2ce08940c5972673ec4dfe88579731ed03</citedby><cites>FETCH-LOGICAL-c375t-ba77a7860ae354f2c3f89010c9a5e9f2ce08940c5972673ec4dfe88579731ed03</cites><orcidid>0000-0003-4032-9049</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s12012-021-09643-4$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s12012-021-09643-4$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33723718$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sen, Pallavi</creatorcontrib><creatorcontrib>Gupta, Kirti</creatorcontrib><creatorcontrib>Kumari, Abha</creatorcontrib><creatorcontrib>Singh, Gaaminepreet</creatorcontrib><creatorcontrib>Pandey, Sneha</creatorcontrib><creatorcontrib>Singh, Ragini</creatorcontrib><title>Wnt/β-Catenin Antagonist Pyrvinium Exerts Cardioprotective Effects in Polymicrobial Sepsis Model by Attenuating Calcium Dyshomeostasis and Mitochondrial Dysfunction</title><title>Cardiovascular toxicology</title><addtitle>Cardiovasc Toxicol</addtitle><addtitle>Cardiovasc Toxicol</addtitle><description>Calcium dysregulation and mitochondrial dysfunction are key elements in the development of sepsis-induced cardiac dysfunction. Evidences have suggested that inhibition of Wnt/β-Catenin signalling prevents cardiac dysfunction and remodelling in surgical, hypertension and pressure overload models. The present study investigated the effects of Wnt/β-Catenin inhibitor on calcium overload and mitochondrial dysfunction in rat sepsis model of cardiomyopathy. Induction of sepsis by cecal ligation puncture (CLP) resulted in the up-regulation of cardiac β-catenin transcriptional levels and cardiac dysfunction depicted by increased serum lactate dehydrogenase, CK-MB levels reduced maximum (d
p
/d
t
max.) and minimum developed pressure (d
p
/d
t
min.), increased LVEsDP and relaxation constant tau values. Moreover, oxidative and inflammatory stress, immune cell infiltration, increased myeloperoxidase activity, enhanced caspase-3 activity and fibronectin protein levels were observed in septic rat’s heart. Also, septic rat’s heart displayed mitochondrial dysfunction due to mPTP opening, increased calcium up-regulation in left ventricular apex tissues and whole heart, increased collagen staining, necrosis and structural damage. Pre-treatment with Wnt/β-Catenin antagonist attenuated sepsis-induced serum and tissue biochemical changes, cardiac dysfunction and structural alterations by inhibiting mitochondrial mPTP opening and restricting calcium overloading in cardiac tissue.</description><subject>Animals</subject><subject>beta Catenin - genetics</subject><subject>beta Catenin - metabolism</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Calcium</subject><subject>Calcium (mitochondrial)</subject><subject>Calcium - metabolism</subject><subject>Calcium homeostasis</subject><subject>Cardiology</subject><subject>Cardiomyopathies - etiology</subject><subject>Cardiomyopathies - metabolism</subject><subject>Cardiomyopathies - physiopathology</subject><subject>Cardiomyopathies - prevention & control</subject><subject>Cardiomyopathy</subject><subject>Caspase-3</subject><subject>Cecum</subject><subject>Coinfection - drug therapy</subject><subject>Coinfection - metabolism</subject><subject>Coinfection - microbiology</subject><subject>Collagen</subject><subject>Cytokines - metabolism</subject><subject>Disease Models, Animal</subject><subject>Fibronectin</subject><subject>Fibrosis</subject><subject>Gene regulation</subject><subject>Heart diseases</subject><subject>Hypertension</subject><subject>Immune system</subject><subject>Inflammation</subject><subject>Inflammation Mediators - metabolism</subject><subject>L-Lactate dehydrogenase</subject><subject>Lactate dehydrogenase</subject><subject>Lactic acid</subject><subject>Male</subject><subject>Mitochondria, Heart - drug effects</subject><subject>Mitochondria, Heart - metabolism</subject><subject>Mitochondria, Heart - pathology</subject><subject>Mitochondrial permeability transition pore</subject><subject>Mitochondrial Permeability Transition Pore - metabolism</subject><subject>Myocytes, Cardiac - drug effects</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>Myocytes, Cardiac - pathology</subject><subject>Necrosis</subject><subject>Overloading</subject><subject>Oxidative Stress - drug effects</subject><subject>Peroxidase</subject><subject>Pharmacology/Toxicology</subject><subject>Pyrvinium Compounds - pharmacology</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Sepsis</subject><subject>Sepsis - drug therapy</subject><subject>Sepsis - metabolism</subject><subject>Sepsis - microbiology</subject><subject>Tissues</subject><subject>Transcription</subject><subject>Ventricle</subject><subject>Ventricular Function, Left - drug effects</subject><subject>Ventricular Pressure - drug effects</subject><subject>Wnt protein</subject><subject>Wnt Signaling Pathway - drug effects</subject><subject>β-Catenin</subject><issn>1530-7905</issn><issn>1559-0259</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp9kctu1DAUhi1ERUvhBVggS2zYhPoSx_FyNAwXqVUrAWJpeZyTqavEHmynIg_EC_AgPBMO04LUBSvfvvMd2z9CLyh5QwmRZ4kyQllFGK2Iampe1Y_QCRVClS2hHi9zTiqpiDhGT1O6IYQx1ogn6Jhzybik7Qn68dXns18_q7XJ4J3HK5_NLniXMr6a463zbhrx5jvEnPDaxM6FfQwZbHa3gDd9X2YJl7qrMMyjszFsnRnwJ9gnl_BF6GDA2xmvcrFPJju_K5bBLtK3c7oOI4SUzcIa3-ELl4O9Dr6Li6QA_eRLp-CfoaPeDAme342n6Mu7zef1h-r88v3H9eq8slyKXG2NlEa2DTHARd0zy_tWEUqsMgJUWQNpVU2sUJI1koOtux7aVkglOYWO8FP0-uAtj_w2Qcp6dMnCMBgPYUqaCUJbQVnNCvrqAXoTpujL7QrFRcMo47RQ7ECVn0kpQq_30Y0mzpoSvYSoDyHqEqL-E6KuS9HLO_W0HaH7W3KfWgH4AUjlyO8g_uv9H-1v6kSrSg</recordid><startdate>20210701</startdate><enddate>20210701</enddate><creator>Sen, Pallavi</creator><creator>Gupta, Kirti</creator><creator>Kumari, Abha</creator><creator>Singh, Gaaminepreet</creator><creator>Pandey, Sneha</creator><creator>Singh, Ragini</creator><general>Springer US</general><general>Springer Nature B.V</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>3V.</scope><scope>7T5</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-4032-9049</orcidid></search><sort><creationdate>20210701</creationdate><title>Wnt/β-Catenin Antagonist Pyrvinium Exerts Cardioprotective Effects in Polymicrobial Sepsis Model by Attenuating Calcium Dyshomeostasis and Mitochondrial Dysfunction</title><author>Sen, Pallavi ; Gupta, Kirti ; Kumari, Abha ; Singh, Gaaminepreet ; Pandey, Sneha ; Singh, Ragini</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c375t-ba77a7860ae354f2c3f89010c9a5e9f2ce08940c5972673ec4dfe88579731ed03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Animals</topic><topic>beta Catenin - genetics</topic><topic>beta Catenin - metabolism</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Calcium</topic><topic>Calcium (mitochondrial)</topic><topic>Calcium - metabolism</topic><topic>Calcium homeostasis</topic><topic>Cardiology</topic><topic>Cardiomyopathies - etiology</topic><topic>Cardiomyopathies - metabolism</topic><topic>Cardiomyopathies - physiopathology</topic><topic>Cardiomyopathies - prevention & control</topic><topic>Cardiomyopathy</topic><topic>Caspase-3</topic><topic>Cecum</topic><topic>Coinfection - drug therapy</topic><topic>Coinfection - metabolism</topic><topic>Coinfection - microbiology</topic><topic>Collagen</topic><topic>Cytokines - metabolism</topic><topic>Disease Models, Animal</topic><topic>Fibronectin</topic><topic>Fibrosis</topic><topic>Gene regulation</topic><topic>Heart diseases</topic><topic>Hypertension</topic><topic>Immune system</topic><topic>Inflammation</topic><topic>Inflammation Mediators - metabolism</topic><topic>L-Lactate dehydrogenase</topic><topic>Lactate dehydrogenase</topic><topic>Lactic acid</topic><topic>Male</topic><topic>Mitochondria, Heart - drug effects</topic><topic>Mitochondria, Heart - metabolism</topic><topic>Mitochondria, Heart - pathology</topic><topic>Mitochondrial permeability transition pore</topic><topic>Mitochondrial Permeability Transition Pore - metabolism</topic><topic>Myocytes, Cardiac - drug effects</topic><topic>Myocytes, Cardiac - metabolism</topic><topic>Myocytes, Cardiac - pathology</topic><topic>Necrosis</topic><topic>Overloading</topic><topic>Oxidative Stress - drug effects</topic><topic>Peroxidase</topic><topic>Pharmacology/Toxicology</topic><topic>Pyrvinium Compounds - pharmacology</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Sepsis</topic><topic>Sepsis - drug therapy</topic><topic>Sepsis - metabolism</topic><topic>Sepsis - microbiology</topic><topic>Tissues</topic><topic>Transcription</topic><topic>Ventricle</topic><topic>Ventricular Function, Left - drug effects</topic><topic>Ventricular Pressure - drug effects</topic><topic>Wnt protein</topic><topic>Wnt Signaling Pathway - drug effects</topic><topic>β-Catenin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sen, Pallavi</creatorcontrib><creatorcontrib>Gupta, Kirti</creatorcontrib><creatorcontrib>Kumari, Abha</creatorcontrib><creatorcontrib>Singh, Gaaminepreet</creatorcontrib><creatorcontrib>Pandey, Sneha</creatorcontrib><creatorcontrib>Singh, Ragini</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>Health & Medical Collection (Proquest)</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</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>MEDLINE - Academic</collection><jtitle>Cardiovascular toxicology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sen, Pallavi</au><au>Gupta, Kirti</au><au>Kumari, Abha</au><au>Singh, Gaaminepreet</au><au>Pandey, Sneha</au><au>Singh, Ragini</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Wnt/β-Catenin Antagonist Pyrvinium Exerts Cardioprotective Effects in Polymicrobial Sepsis Model by Attenuating Calcium Dyshomeostasis and Mitochondrial Dysfunction</atitle><jtitle>Cardiovascular toxicology</jtitle><stitle>Cardiovasc Toxicol</stitle><addtitle>Cardiovasc Toxicol</addtitle><date>2021-07-01</date><risdate>2021</risdate><volume>21</volume><issue>7</issue><spage>517</spage><epage>532</epage><pages>517-532</pages><issn>1530-7905</issn><eissn>1559-0259</eissn><abstract>Calcium dysregulation and mitochondrial dysfunction are key elements in the development of sepsis-induced cardiac dysfunction. Evidences have suggested that inhibition of Wnt/β-Catenin signalling prevents cardiac dysfunction and remodelling in surgical, hypertension and pressure overload models. The present study investigated the effects of Wnt/β-Catenin inhibitor on calcium overload and mitochondrial dysfunction in rat sepsis model of cardiomyopathy. Induction of sepsis by cecal ligation puncture (CLP) resulted in the up-regulation of cardiac β-catenin transcriptional levels and cardiac dysfunction depicted by increased serum lactate dehydrogenase, CK-MB levels reduced maximum (d
p
/d
t
max.) and minimum developed pressure (d
p
/d
t
min.), increased LVEsDP and relaxation constant tau values. Moreover, oxidative and inflammatory stress, immune cell infiltration, increased myeloperoxidase activity, enhanced caspase-3 activity and fibronectin protein levels were observed in septic rat’s heart. Also, septic rat’s heart displayed mitochondrial dysfunction due to mPTP opening, increased calcium up-regulation in left ventricular apex tissues and whole heart, increased collagen staining, necrosis and structural damage. Pre-treatment with Wnt/β-Catenin antagonist attenuated sepsis-induced serum and tissue biochemical changes, cardiac dysfunction and structural alterations by inhibiting mitochondrial mPTP opening and restricting calcium overloading in cardiac tissue.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>33723718</pmid><doi>10.1007/s12012-021-09643-4</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0003-4032-9049</orcidid></addata></record> |
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| ispartof | Cardiovascular toxicology, 2021-07, Vol.21 (7), p.517-532 |
| issn | 1530-7905 1559-0259 |
| language | eng |
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| source | MEDLINE; SpringerLink Journals - AutoHoldings |
| subjects | Animals beta Catenin - genetics beta Catenin - metabolism Biomedical and Life Sciences Biomedicine Calcium Calcium (mitochondrial) Calcium - metabolism Calcium homeostasis Cardiology Cardiomyopathies - etiology Cardiomyopathies - metabolism Cardiomyopathies - physiopathology Cardiomyopathies - prevention & control Cardiomyopathy Caspase-3 Cecum Coinfection - drug therapy Coinfection - metabolism Coinfection - microbiology Collagen Cytokines - metabolism Disease Models, Animal Fibronectin Fibrosis Gene regulation Heart diseases Hypertension Immune system Inflammation Inflammation Mediators - metabolism L-Lactate dehydrogenase Lactate dehydrogenase Lactic acid Male Mitochondria, Heart - drug effects Mitochondria, Heart - metabolism Mitochondria, Heart - pathology Mitochondrial permeability transition pore Mitochondrial Permeability Transition Pore - metabolism Myocytes, Cardiac - drug effects Myocytes, Cardiac - metabolism Myocytes, Cardiac - pathology Necrosis Overloading Oxidative Stress - drug effects Peroxidase Pharmacology/Toxicology Pyrvinium Compounds - pharmacology Rats Rats, Wistar Sepsis Sepsis - drug therapy Sepsis - metabolism Sepsis - microbiology Tissues Transcription Ventricle Ventricular Function, Left - drug effects Ventricular Pressure - drug effects Wnt protein Wnt Signaling Pathway - drug effects β-Catenin |
| title | Wnt/β-Catenin Antagonist Pyrvinium Exerts Cardioprotective Effects in Polymicrobial Sepsis Model by Attenuating Calcium Dyshomeostasis and Mitochondrial Dysfunction |
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