Cell cycle re-entry and mitochondrial defects in myc-mediated hypertrophic cardiomyopathy and heart failure

While considerable evidence supports the causal relationship between increases in c-Myc (Myc) and cardiomyopathy as a part of a "fetal re-expression" pattern, the functional role of Myc in mechanisms of cardiomyopathy remains unclear. To address this, we developed a bitransgenic mouse that...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:PloS one 2009-09, Vol.4 (9), p.e7172-e7172
Hauptverfasser: Lee, Hyoung-gon, Chen, Qun, Wolfram, Julie A, Richardson, Sandy L, Liner, Anna, Siedlak, Sandra L, Zhu, Xiongwei, Ziats, Nicholas P, Fujioka, Hisashi, Felsher, Dean W, Castellani, Rudy J, Valencik, Maria L, McDonald, John A, Hoit, Brian D, Lesnefsky, Edward J, Smith, Mark A
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page e7172
container_issue 9
container_start_page e7172
container_title PloS one
container_volume 4
creator Lee, Hyoung-gon
Chen, Qun
Wolfram, Julie A
Richardson, Sandy L
Liner, Anna
Siedlak, Sandra L
Zhu, Xiongwei
Ziats, Nicholas P
Fujioka, Hisashi
Felsher, Dean W
Castellani, Rudy J
Valencik, Maria L
McDonald, John A
Hoit, Brian D
Lesnefsky, Edward J
Smith, Mark A
description While considerable evidence supports the causal relationship between increases in c-Myc (Myc) and cardiomyopathy as a part of a "fetal re-expression" pattern, the functional role of Myc in mechanisms of cardiomyopathy remains unclear. To address this, we developed a bitransgenic mouse that inducibly expresses Myc under the control of the cardiomyocyte-specific MHC promoter. In adult mice the induction of Myc expression in cardiomyocytes in the heart led to the development of severe hypertrophic cardiomyopathy followed by ventricular dysfunction and ultimately death from congestive heart failure. Mechanistically, following Myc activation, cell cycle markers and other indices of DNA replication were significantly increased suggesting that cell cycle-related events might be a primary mechanism of cardiac dysfunction. Furthermore, pathological alterations at the cellular level included alterations in mitochondrial function with dysregulation of mitochondrial biogenesis and defects in electron transport chain complexes I and III. These data are consistent with the known role of Myc in several different pathways including cell cycle activation, mitochondrial proliferation, and apoptosis, and indicate that Myc activation in cardiomyocytes is an important regulator of downstream pathological sequelae. Moreover, our findings indicate that the induction of Myc in cardiomyocytes is sufficient to cause cardiomyopathy and heart failure, and that sustained induction of Myc, leading to cell cycle re-entry in adult cardiomyocytes, represents a maladaptive response for the mature heart.
doi_str_mv 10.1371/journal.pone.0007172
format Article
fullrecord <record><control><sourceid>gale_plos_</sourceid><recordid>TN_cdi_plos_journals_1292103356</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A472860508</galeid><doaj_id>oai_doaj_org_article_9ab82388ceff4f3d8d97745aec42e465</doaj_id><sourcerecordid>A472860508</sourcerecordid><originalsourceid>FETCH-LOGICAL-c729t-4f34ddd82e5ce17a6c70d60d9efa95ccfa47b7d687d390b2f5cd5af1ce8672423</originalsourceid><addsrcrecordid>eNqNkl2L1DAUhoso7jr6D0QLguJFxzRpm-ZGWAY_BhYW_LoNmeRkmrFtukkq9t-bsVVnxAvJRULynDcnb94keZyjdU5o_upgR9eLdj3YHtYIIZpTfCe5zBnBWYURuXuyvkgeeH9AqCR1Vd1PLnJGKaswu0y-bqBtUznJFlIHGfTBTanoVdqZYGVje-WMaFMFGmTwqenTbpJZB8qIACptpgFccHZojEylcMrYbrKDCM2s0oBwIdXCtKODh8k9LVoPj5Z5lXx---bT5n12ffNuu7m6ziTFLGSFJoVSqsZQSsipqCRFqkKKgRaslFKLgu6oqmqqCEM7rEupSqFzCXVFcYHJKnk66w6t9XzxyfMcM5wjQsoqEtuZUFYc-OBMJ9zErTD854Z1ex77NtEUzsSuxqSuJWgdO1O1it4VpQBZYCiqMmq9Xm4bd9EXebRQtGei5ye9afjefuOYFhTFflbJi0XA2dsRfOCd8TJ-i-jBjp5TUqCSMUIj-ewv8t-PW8_UXsT-Ta9tvFbGoaAzMqZFm7h_VVBcV6hEdSx4eVYQmQDfw16M3vPtxw__z958OWefn7AxCm1ovG3HYGzvz8FiBqWz3jvQv93LET-G_dc7-THsfAl7LHty6vyfoiXd5Aentf1G</addsrcrecordid><sourcetype>Open Website</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1292103356</pqid></control><display><type>article</type><title>Cell cycle re-entry and mitochondrial defects in myc-mediated hypertrophic cardiomyopathy and heart failure</title><source>MEDLINE</source><source>DOAJ Directory of Open Access Journals</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Public Library of Science (PLoS)</source><source>PubMed Central</source><source>Free Full-Text Journals in Chemistry</source><creator>Lee, Hyoung-gon ; Chen, Qun ; Wolfram, Julie A ; Richardson, Sandy L ; Liner, Anna ; Siedlak, Sandra L ; Zhu, Xiongwei ; Ziats, Nicholas P ; Fujioka, Hisashi ; Felsher, Dean W ; Castellani, Rudy J ; Valencik, Maria L ; McDonald, John A ; Hoit, Brian D ; Lesnefsky, Edward J ; Smith, Mark A</creator><contributor>Kowaltowski, Alicia J.</contributor><creatorcontrib>Lee, Hyoung-gon ; Chen, Qun ; Wolfram, Julie A ; Richardson, Sandy L ; Liner, Anna ; Siedlak, Sandra L ; Zhu, Xiongwei ; Ziats, Nicholas P ; Fujioka, Hisashi ; Felsher, Dean W ; Castellani, Rudy J ; Valencik, Maria L ; McDonald, John A ; Hoit, Brian D ; Lesnefsky, Edward J ; Smith, Mark A ; Kowaltowski, Alicia J.</creatorcontrib><description>While considerable evidence supports the causal relationship between increases in c-Myc (Myc) and cardiomyopathy as a part of a "fetal re-expression" pattern, the functional role of Myc in mechanisms of cardiomyopathy remains unclear. To address this, we developed a bitransgenic mouse that inducibly expresses Myc under the control of the cardiomyocyte-specific MHC promoter. In adult mice the induction of Myc expression in cardiomyocytes in the heart led to the development of severe hypertrophic cardiomyopathy followed by ventricular dysfunction and ultimately death from congestive heart failure. Mechanistically, following Myc activation, cell cycle markers and other indices of DNA replication were significantly increased suggesting that cell cycle-related events might be a primary mechanism of cardiac dysfunction. Furthermore, pathological alterations at the cellular level included alterations in mitochondrial function with dysregulation of mitochondrial biogenesis and defects in electron transport chain complexes I and III. These data are consistent with the known role of Myc in several different pathways including cell cycle activation, mitochondrial proliferation, and apoptosis, and indicate that Myc activation in cardiomyocytes is an important regulator of downstream pathological sequelae. Moreover, our findings indicate that the induction of Myc in cardiomyocytes is sufficient to cause cardiomyopathy and heart failure, and that sustained induction of Myc, leading to cell cycle re-entry in adult cardiomyocytes, represents a maladaptive response for the mature heart.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0007172</identifier><identifier>PMID: 19779629</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Aging ; Alterations ; Alzheimer's disease ; Alzheimers disease ; Animals ; Apoptosis ; Biochemistry ; c-Myc protein ; Cardiomyocytes ; Cardiomyopathy ; Cardiomyopathy, Hypertrophic - metabolism ; Cardiovascular Disorders/Heart Failure ; Cardiovascular Disorders/Myopathies ; Cell activation ; Cell Cycle ; Cell Proliferation ; Complications ; Congestive heart failure ; Cyclin-dependent kinases ; Cytochrome ; Defects ; Dehydrogenases ; Deoxyribonucleic acid ; DNA ; DNA biosynthesis ; DNA replication ; Electron Transport ; Electron transport chain ; Female ; Fetuses ; Heart ; Heart attacks ; Heart failure ; Heart Failure - metabolism ; Hypertrophic cardiomyopathy ; Hypertrophy ; Kinases ; Major histocompatibility complex ; Medicine ; Mice ; Mice, Transgenic ; Mitochondria ; Mitochondria - metabolism ; Mitochondria - pathology ; Mitochondrial DNA ; Models, Biological ; Multiple myeloma ; Myc protein ; Myocytes, Cardiac - cytology ; Pathology ; Physiology/Muscle and Connective Tissue ; Promoter Regions, Genetic ; Proto-Oncogene Proteins c-myc - metabolism ; Rodents ; Ventricle</subject><ispartof>PloS one, 2009-09, Vol.4 (9), p.e7172-e7172</ispartof><rights>COPYRIGHT 2009 Public Library of Science</rights><rights>2009 Lee et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (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>Lee et al. 2009</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c729t-4f34ddd82e5ce17a6c70d60d9efa95ccfa47b7d687d390b2f5cd5af1ce8672423</citedby><cites>FETCH-LOGICAL-c729t-4f34ddd82e5ce17a6c70d60d9efa95ccfa47b7d687d390b2f5cd5af1ce8672423</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/PMC2747003/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2747003/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,729,782,786,866,887,2104,2930,23873,27931,27932,53798,53800</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19779629$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Kowaltowski, Alicia J.</contributor><creatorcontrib>Lee, Hyoung-gon</creatorcontrib><creatorcontrib>Chen, Qun</creatorcontrib><creatorcontrib>Wolfram, Julie A</creatorcontrib><creatorcontrib>Richardson, Sandy L</creatorcontrib><creatorcontrib>Liner, Anna</creatorcontrib><creatorcontrib>Siedlak, Sandra L</creatorcontrib><creatorcontrib>Zhu, Xiongwei</creatorcontrib><creatorcontrib>Ziats, Nicholas P</creatorcontrib><creatorcontrib>Fujioka, Hisashi</creatorcontrib><creatorcontrib>Felsher, Dean W</creatorcontrib><creatorcontrib>Castellani, Rudy J</creatorcontrib><creatorcontrib>Valencik, Maria L</creatorcontrib><creatorcontrib>McDonald, John A</creatorcontrib><creatorcontrib>Hoit, Brian D</creatorcontrib><creatorcontrib>Lesnefsky, Edward J</creatorcontrib><creatorcontrib>Smith, Mark A</creatorcontrib><title>Cell cycle re-entry and mitochondrial defects in myc-mediated hypertrophic cardiomyopathy and heart failure</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>While considerable evidence supports the causal relationship between increases in c-Myc (Myc) and cardiomyopathy as a part of a "fetal re-expression" pattern, the functional role of Myc in mechanisms of cardiomyopathy remains unclear. To address this, we developed a bitransgenic mouse that inducibly expresses Myc under the control of the cardiomyocyte-specific MHC promoter. In adult mice the induction of Myc expression in cardiomyocytes in the heart led to the development of severe hypertrophic cardiomyopathy followed by ventricular dysfunction and ultimately death from congestive heart failure. Mechanistically, following Myc activation, cell cycle markers and other indices of DNA replication were significantly increased suggesting that cell cycle-related events might be a primary mechanism of cardiac dysfunction. Furthermore, pathological alterations at the cellular level included alterations in mitochondrial function with dysregulation of mitochondrial biogenesis and defects in electron transport chain complexes I and III. These data are consistent with the known role of Myc in several different pathways including cell cycle activation, mitochondrial proliferation, and apoptosis, and indicate that Myc activation in cardiomyocytes is an important regulator of downstream pathological sequelae. Moreover, our findings indicate that the induction of Myc in cardiomyocytes is sufficient to cause cardiomyopathy and heart failure, and that sustained induction of Myc, leading to cell cycle re-entry in adult cardiomyocytes, represents a maladaptive response for the mature heart.</description><subject>Aging</subject><subject>Alterations</subject><subject>Alzheimer's disease</subject><subject>Alzheimers disease</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Biochemistry</subject><subject>c-Myc protein</subject><subject>Cardiomyocytes</subject><subject>Cardiomyopathy</subject><subject>Cardiomyopathy, Hypertrophic - metabolism</subject><subject>Cardiovascular Disorders/Heart Failure</subject><subject>Cardiovascular Disorders/Myopathies</subject><subject>Cell activation</subject><subject>Cell Cycle</subject><subject>Cell Proliferation</subject><subject>Complications</subject><subject>Congestive heart failure</subject><subject>Cyclin-dependent kinases</subject><subject>Cytochrome</subject><subject>Defects</subject><subject>Dehydrogenases</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA biosynthesis</subject><subject>DNA replication</subject><subject>Electron Transport</subject><subject>Electron transport chain</subject><subject>Female</subject><subject>Fetuses</subject><subject>Heart</subject><subject>Heart attacks</subject><subject>Heart failure</subject><subject>Heart Failure - metabolism</subject><subject>Hypertrophic cardiomyopathy</subject><subject>Hypertrophy</subject><subject>Kinases</subject><subject>Major histocompatibility complex</subject><subject>Medicine</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Mitochondria</subject><subject>Mitochondria - metabolism</subject><subject>Mitochondria - pathology</subject><subject>Mitochondrial DNA</subject><subject>Models, Biological</subject><subject>Multiple myeloma</subject><subject>Myc protein</subject><subject>Myocytes, Cardiac - cytology</subject><subject>Pathology</subject><subject>Physiology/Muscle and Connective Tissue</subject><subject>Promoter Regions, Genetic</subject><subject>Proto-Oncogene Proteins c-myc - metabolism</subject><subject>Rodents</subject><subject>Ventricle</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</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>eNqNkl2L1DAUhoso7jr6D0QLguJFxzRpm-ZGWAY_BhYW_LoNmeRkmrFtukkq9t-bsVVnxAvJRULynDcnb94keZyjdU5o_upgR9eLdj3YHtYIIZpTfCe5zBnBWYURuXuyvkgeeH9AqCR1Vd1PLnJGKaswu0y-bqBtUznJFlIHGfTBTanoVdqZYGVje-WMaFMFGmTwqenTbpJZB8qIACptpgFccHZojEylcMrYbrKDCM2s0oBwIdXCtKODh8k9LVoPj5Z5lXx---bT5n12ffNuu7m6ziTFLGSFJoVSqsZQSsipqCRFqkKKgRaslFKLgu6oqmqqCEM7rEupSqFzCXVFcYHJKnk66w6t9XzxyfMcM5wjQsoqEtuZUFYc-OBMJ9zErTD854Z1ex77NtEUzsSuxqSuJWgdO1O1it4VpQBZYCiqMmq9Xm4bd9EXebRQtGei5ye9afjefuOYFhTFflbJi0XA2dsRfOCd8TJ-i-jBjp5TUqCSMUIj-ewv8t-PW8_UXsT-Ta9tvFbGoaAzMqZFm7h_VVBcV6hEdSx4eVYQmQDfw16M3vPtxw__z958OWefn7AxCm1ovG3HYGzvz8FiBqWz3jvQv93LET-G_dc7-THsfAl7LHty6vyfoiXd5Aentf1G</recordid><startdate>20090925</startdate><enddate>20090925</enddate><creator>Lee, Hyoung-gon</creator><creator>Chen, Qun</creator><creator>Wolfram, Julie A</creator><creator>Richardson, Sandy L</creator><creator>Liner, Anna</creator><creator>Siedlak, Sandra L</creator><creator>Zhu, Xiongwei</creator><creator>Ziats, Nicholas P</creator><creator>Fujioka, Hisashi</creator><creator>Felsher, Dean W</creator><creator>Castellani, Rudy J</creator><creator>Valencik, Maria L</creator><creator>McDonald, John A</creator><creator>Hoit, Brian D</creator><creator>Lesnefsky, Edward J</creator><creator>Smith, Mark A</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>20090925</creationdate><title>Cell cycle re-entry and mitochondrial defects in myc-mediated hypertrophic cardiomyopathy and heart failure</title><author>Lee, Hyoung-gon ; Chen, Qun ; Wolfram, Julie A ; Richardson, Sandy L ; Liner, Anna ; Siedlak, Sandra L ; Zhu, Xiongwei ; Ziats, Nicholas P ; Fujioka, Hisashi ; Felsher, Dean W ; Castellani, Rudy J ; Valencik, Maria L ; McDonald, John A ; Hoit, Brian D ; Lesnefsky, Edward J ; Smith, Mark A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c729t-4f34ddd82e5ce17a6c70d60d9efa95ccfa47b7d687d390b2f5cd5af1ce8672423</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Aging</topic><topic>Alterations</topic><topic>Alzheimer's disease</topic><topic>Alzheimers disease</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Biochemistry</topic><topic>c-Myc protein</topic><topic>Cardiomyocytes</topic><topic>Cardiomyopathy</topic><topic>Cardiomyopathy, Hypertrophic - metabolism</topic><topic>Cardiovascular Disorders/Heart Failure</topic><topic>Cardiovascular Disorders/Myopathies</topic><topic>Cell activation</topic><topic>Cell Cycle</topic><topic>Cell Proliferation</topic><topic>Complications</topic><topic>Congestive heart failure</topic><topic>Cyclin-dependent kinases</topic><topic>Cytochrome</topic><topic>Defects</topic><topic>Dehydrogenases</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA biosynthesis</topic><topic>DNA replication</topic><topic>Electron Transport</topic><topic>Electron transport chain</topic><topic>Female</topic><topic>Fetuses</topic><topic>Heart</topic><topic>Heart attacks</topic><topic>Heart failure</topic><topic>Heart Failure - metabolism</topic><topic>Hypertrophic cardiomyopathy</topic><topic>Hypertrophy</topic><topic>Kinases</topic><topic>Major histocompatibility complex</topic><topic>Medicine</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Mitochondria</topic><topic>Mitochondria - metabolism</topic><topic>Mitochondria - pathology</topic><topic>Mitochondrial DNA</topic><topic>Models, Biological</topic><topic>Multiple myeloma</topic><topic>Myc protein</topic><topic>Myocytes, Cardiac - cytology</topic><topic>Pathology</topic><topic>Physiology/Muscle and Connective Tissue</topic><topic>Promoter Regions, Genetic</topic><topic>Proto-Oncogene Proteins c-myc - metabolism</topic><topic>Rodents</topic><topic>Ventricle</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lee, Hyoung-gon</creatorcontrib><creatorcontrib>Chen, Qun</creatorcontrib><creatorcontrib>Wolfram, Julie A</creatorcontrib><creatorcontrib>Richardson, Sandy L</creatorcontrib><creatorcontrib>Liner, Anna</creatorcontrib><creatorcontrib>Siedlak, Sandra L</creatorcontrib><creatorcontrib>Zhu, Xiongwei</creatorcontrib><creatorcontrib>Ziats, Nicholas P</creatorcontrib><creatorcontrib>Fujioka, Hisashi</creatorcontrib><creatorcontrib>Felsher, Dean W</creatorcontrib><creatorcontrib>Castellani, Rudy J</creatorcontrib><creatorcontrib>Valencik, Maria L</creatorcontrib><creatorcontrib>McDonald, John A</creatorcontrib><creatorcontrib>Hoit, Brian D</creatorcontrib><creatorcontrib>Lesnefsky, Edward J</creatorcontrib><creatorcontrib>Smith, Mark A</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing &amp; Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological &amp; Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health &amp; Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science &amp; Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies &amp; Aerospace Collection</collection><collection>Agricultural &amp; Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing &amp; Allied Health Database (Alumni Edition)</collection><collection>Meteorological &amp; Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing &amp; Allied Health Premium</collection><collection>Advanced Technologies &amp; Aerospace Database</collection><collection>ProQuest Advanced Technologies &amp; 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>Lee, Hyoung-gon</au><au>Chen, Qun</au><au>Wolfram, Julie A</au><au>Richardson, Sandy L</au><au>Liner, Anna</au><au>Siedlak, Sandra L</au><au>Zhu, Xiongwei</au><au>Ziats, Nicholas P</au><au>Fujioka, Hisashi</au><au>Felsher, Dean W</au><au>Castellani, Rudy J</au><au>Valencik, Maria L</au><au>McDonald, John A</au><au>Hoit, Brian D</au><au>Lesnefsky, Edward J</au><au>Smith, Mark A</au><au>Kowaltowski, Alicia J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cell cycle re-entry and mitochondrial defects in myc-mediated hypertrophic cardiomyopathy and heart failure</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2009-09-25</date><risdate>2009</risdate><volume>4</volume><issue>9</issue><spage>e7172</spage><epage>e7172</epage><pages>e7172-e7172</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>While considerable evidence supports the causal relationship between increases in c-Myc (Myc) and cardiomyopathy as a part of a "fetal re-expression" pattern, the functional role of Myc in mechanisms of cardiomyopathy remains unclear. To address this, we developed a bitransgenic mouse that inducibly expresses Myc under the control of the cardiomyocyte-specific MHC promoter. In adult mice the induction of Myc expression in cardiomyocytes in the heart led to the development of severe hypertrophic cardiomyopathy followed by ventricular dysfunction and ultimately death from congestive heart failure. Mechanistically, following Myc activation, cell cycle markers and other indices of DNA replication were significantly increased suggesting that cell cycle-related events might be a primary mechanism of cardiac dysfunction. Furthermore, pathological alterations at the cellular level included alterations in mitochondrial function with dysregulation of mitochondrial biogenesis and defects in electron transport chain complexes I and III. These data are consistent with the known role of Myc in several different pathways including cell cycle activation, mitochondrial proliferation, and apoptosis, and indicate that Myc activation in cardiomyocytes is an important regulator of downstream pathological sequelae. Moreover, our findings indicate that the induction of Myc in cardiomyocytes is sufficient to cause cardiomyopathy and heart failure, and that sustained induction of Myc, leading to cell cycle re-entry in adult cardiomyocytes, represents a maladaptive response for the mature heart.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>19779629</pmid><doi>10.1371/journal.pone.0007172</doi><tpages>e7172</tpages><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 1932-6203
ispartof PloS one, 2009-09, Vol.4 (9), p.e7172-e7172
issn 1932-6203
1932-6203
language eng
recordid cdi_plos_journals_1292103356
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 Aging
Alterations
Alzheimer's disease
Alzheimers disease
Animals
Apoptosis
Biochemistry
c-Myc protein
Cardiomyocytes
Cardiomyopathy
Cardiomyopathy, Hypertrophic - metabolism
Cardiovascular Disorders/Heart Failure
Cardiovascular Disorders/Myopathies
Cell activation
Cell Cycle
Cell Proliferation
Complications
Congestive heart failure
Cyclin-dependent kinases
Cytochrome
Defects
Dehydrogenases
Deoxyribonucleic acid
DNA
DNA biosynthesis
DNA replication
Electron Transport
Electron transport chain
Female
Fetuses
Heart
Heart attacks
Heart failure
Heart Failure - metabolism
Hypertrophic cardiomyopathy
Hypertrophy
Kinases
Major histocompatibility complex
Medicine
Mice
Mice, Transgenic
Mitochondria
Mitochondria - metabolism
Mitochondria - pathology
Mitochondrial DNA
Models, Biological
Multiple myeloma
Myc protein
Myocytes, Cardiac - cytology
Pathology
Physiology/Muscle and Connective Tissue
Promoter Regions, Genetic
Proto-Oncogene Proteins c-myc - metabolism
Rodents
Ventricle
title Cell cycle re-entry and mitochondrial defects in myc-mediated hypertrophic cardiomyopathy and heart failure
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-08T16%3A01%3A37IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Cell%20cycle%20re-entry%20and%20mitochondrial%20defects%20in%20myc-mediated%20hypertrophic%20cardiomyopathy%20and%20heart%20failure&rft.jtitle=PloS%20one&rft.au=Lee,%20Hyoung-gon&rft.date=2009-09-25&rft.volume=4&rft.issue=9&rft.spage=e7172&rft.epage=e7172&rft.pages=e7172-e7172&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0007172&rft_dat=%3Cgale_plos_%3EA472860508%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1292103356&rft_id=info:pmid/19779629&rft_galeid=A472860508&rft_doaj_id=oai_doaj_org_article_9ab82388ceff4f3d8d97745aec42e465&rfr_iscdi=true