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...

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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
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container_issue 9
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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
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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. 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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. 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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>
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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
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