MEF2C silencing attenuates load-induced left ventricular hypertrophy by modulating mTOR/S6K pathway in mice
The activation of the members of the myocyte enhancer factor-2 family (MEF2A, B, C and D) of transcription factors promotes cardiac hypertrophy and failure. However, the role of its individual components in the pathogenesis of cardiac hypertrophy remains unclear. In this study, we investigated wheth...
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creator | Pereira, Ana Helena M Clemente, Carolina F M Z Cardoso, Alisson C Theizen, Thais H Rocco, Silvana A Judice, Carla C Guido, Maria Carolina Pascoal, Vinícius D B Lopes-Cendes, Iscia Souza, José Roberto M Franchini, Kleber G |
description | The activation of the members of the myocyte enhancer factor-2 family (MEF2A, B, C and D) of transcription factors promotes cardiac hypertrophy and failure. However, the role of its individual components in the pathogenesis of cardiac hypertrophy remains unclear.
In this study, we investigated whether MEF2C plays a role in mediating the left ventricular hypertrophy by pressure overload in mice. The knockdown of myocardial MEF2C induced by specific small interfering RNA (siRNA) has been shown to attenuate hypertrophy, interstitial fibrosis and the rise of ANP levels in aortic banded mice. We detected that the depletion of MEF2C also results in lowered levels of both PGC-1alpha and mitochondrial DNA in the overloaded left ventricle, associated with enhanced AMP:ATP ratio. Additionally, MEF2C depletion was accompanied by defective activation of S6K in response to pressure overload. Treatment with the amino acid leucine stimulated S6K and suppressed the attenuation of left ventricular hypertrophy and fibrosis in the aforementioned aortic banded mice.
These findings represent new evidences that MEF2C depletion attenuates the hypertrophic responses to mechanical stress and highlight the potential of MEF2C to be a target for new therapies to cardiac hypertrophy and failure. |
doi_str_mv | 10.1371/journal.pone.0008472 |
format | Article |
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In this study, we investigated whether MEF2C plays a role in mediating the left ventricular hypertrophy by pressure overload in mice. The knockdown of myocardial MEF2C induced by specific small interfering RNA (siRNA) has been shown to attenuate hypertrophy, interstitial fibrosis and the rise of ANP levels in aortic banded mice. We detected that the depletion of MEF2C also results in lowered levels of both PGC-1alpha and mitochondrial DNA in the overloaded left ventricle, associated with enhanced AMP:ATP ratio. Additionally, MEF2C depletion was accompanied by defective activation of S6K in response to pressure overload. Treatment with the amino acid leucine stimulated S6K and suppressed the attenuation of left ventricular hypertrophy and fibrosis in the aforementioned aortic banded mice.
These findings represent new evidences that MEF2C depletion attenuates the hypertrophic responses to mechanical stress and highlight the potential of MEF2C to be a target for new therapies to cardiac hypertrophy and failure.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0008472</identifier><identifier>PMID: 20041152</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Activation ; Amino acids ; AMP ; Animals ; Aorta ; Atherosclerosis ; Attenuation ; Biochemistry/Cell Signaling and Trafficking Structures ; Biochemistry/Transcription and Translation ; Biosynthesis ; Cardiomyocytes ; Cardiomyopathy ; Cardiovascular Disorders/Heart Failure ; Cell Biology/Cell Growth and Division ; Cell growth ; Cells, Cultured ; Deoxyribonucleic acid ; Depletion ; DNA ; DNA binding proteins ; DNA, Mitochondrial - genetics ; Fibrosis ; Gene Silencing ; Heart ; Heart diseases ; Heart failure ; Heart hypertrophy ; Hemodynamics ; Hypertrophy ; Hypertrophy, Left Ventricular - enzymology ; Hypertrophy, Left Ventricular - physiopathology ; Internal medicine ; Intracellular Signaling Peptides and Proteins - metabolism ; Kinases ; Leucine ; Medicine ; MEF2 Transcription Factors ; Mice ; Mitochondrial DNA ; Myocardium - enzymology ; Myocardium - pathology ; Myocytes, Cardiac - metabolism ; Myocytes, Cardiac - pathology ; Myogenic Regulatory Factors - genetics ; Myogenic Regulatory Factors - metabolism ; Pathogenesis ; Pressure ; Protein expression ; Protein synthesis ; Protein-Serine-Threonine Kinases - metabolism ; Proteins ; Rats ; Ribonucleic acid ; Ribosomal Protein S6 Kinases, 90-kDa - metabolism ; RNA ; RNA, Small Interfering - metabolism ; Rodents ; Signal Transduction ; siRNA ; Stem cells ; TOR protein ; TOR Serine-Threonine Kinases ; Transcription factors ; Ventricle ; Ventricular Pressure - physiology</subject><ispartof>PloS one, 2009-12, Vol.4 (12), p.e8472-e8472</ispartof><rights>COPYRIGHT 2009 Public Library of Science</rights><rights>2009 Pereira 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>Pereira et al. 2009</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c729t-b93a6f1200f318bb0f6a36dfaa3e7b2f1a0dd121ce428c66c147bdb749ab06153</citedby><cites>FETCH-LOGICAL-c729t-b93a6f1200f318bb0f6a36dfaa3e7b2f1a0dd121ce428c66c147bdb749ab06153</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/PMC2794538/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2794538/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20041152$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Schwartz, Arnold</contributor><creatorcontrib>Pereira, Ana Helena M</creatorcontrib><creatorcontrib>Clemente, Carolina F M Z</creatorcontrib><creatorcontrib>Cardoso, Alisson C</creatorcontrib><creatorcontrib>Theizen, Thais H</creatorcontrib><creatorcontrib>Rocco, Silvana A</creatorcontrib><creatorcontrib>Judice, Carla C</creatorcontrib><creatorcontrib>Guido, Maria Carolina</creatorcontrib><creatorcontrib>Pascoal, Vinícius D B</creatorcontrib><creatorcontrib>Lopes-Cendes, Iscia</creatorcontrib><creatorcontrib>Souza, José Roberto M</creatorcontrib><creatorcontrib>Franchini, Kleber G</creatorcontrib><title>MEF2C silencing attenuates load-induced left ventricular hypertrophy by modulating mTOR/S6K pathway in mice</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The activation of the members of the myocyte enhancer factor-2 family (MEF2A, B, C and D) of transcription factors promotes cardiac hypertrophy and failure. However, the role of its individual components in the pathogenesis of cardiac hypertrophy remains unclear.
In this study, we investigated whether MEF2C plays a role in mediating the left ventricular hypertrophy by pressure overload in mice. The knockdown of myocardial MEF2C induced by specific small interfering RNA (siRNA) has been shown to attenuate hypertrophy, interstitial fibrosis and the rise of ANP levels in aortic banded mice. We detected that the depletion of MEF2C also results in lowered levels of both PGC-1alpha and mitochondrial DNA in the overloaded left ventricle, associated with enhanced AMP:ATP ratio. Additionally, MEF2C depletion was accompanied by defective activation of S6K in response to pressure overload. Treatment with the amino acid leucine stimulated S6K and suppressed the attenuation of left ventricular hypertrophy and fibrosis in the aforementioned aortic banded mice.
These findings represent new evidences that MEF2C depletion attenuates the hypertrophic responses to mechanical stress and highlight the potential of MEF2C to be a target for new therapies to cardiac hypertrophy and failure.</description><subject>Activation</subject><subject>Amino acids</subject><subject>AMP</subject><subject>Animals</subject><subject>Aorta</subject><subject>Atherosclerosis</subject><subject>Attenuation</subject><subject>Biochemistry/Cell Signaling and Trafficking Structures</subject><subject>Biochemistry/Transcription and Translation</subject><subject>Biosynthesis</subject><subject>Cardiomyocytes</subject><subject>Cardiomyopathy</subject><subject>Cardiovascular Disorders/Heart Failure</subject><subject>Cell Biology/Cell Growth and Division</subject><subject>Cell growth</subject><subject>Cells, Cultured</subject><subject>Deoxyribonucleic acid</subject><subject>Depletion</subject><subject>DNA</subject><subject>DNA binding proteins</subject><subject>DNA, Mitochondrial - genetics</subject><subject>Fibrosis</subject><subject>Gene Silencing</subject><subject>Heart</subject><subject>Heart diseases</subject><subject>Heart failure</subject><subject>Heart hypertrophy</subject><subject>Hemodynamics</subject><subject>Hypertrophy</subject><subject>Hypertrophy, Left Ventricular - enzymology</subject><subject>Hypertrophy, Left Ventricular - physiopathology</subject><subject>Internal medicine</subject><subject>Intracellular Signaling Peptides and Proteins - metabolism</subject><subject>Kinases</subject><subject>Leucine</subject><subject>Medicine</subject><subject>MEF2 Transcription Factors</subject><subject>Mice</subject><subject>Mitochondrial DNA</subject><subject>Myocardium - enzymology</subject><subject>Myocardium - pathology</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>Myocytes, Cardiac - pathology</subject><subject>Myogenic Regulatory Factors - genetics</subject><subject>Myogenic Regulatory Factors - metabolism</subject><subject>Pathogenesis</subject><subject>Pressure</subject><subject>Protein expression</subject><subject>Protein synthesis</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Proteins</subject><subject>Rats</subject><subject>Ribonucleic acid</subject><subject>Ribosomal Protein S6 Kinases, 90-kDa - metabolism</subject><subject>RNA</subject><subject>RNA, Small Interfering - metabolism</subject><subject>Rodents</subject><subject>Signal Transduction</subject><subject>siRNA</subject><subject>Stem cells</subject><subject>TOR protein</subject><subject>TOR Serine-Threonine Kinases</subject><subject>Transcription factors</subject><subject>Ventricle</subject><subject>Ventricular Pressure - physiology</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>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNkl9v0zAUxSMEYmPwDRBYQgLx0M5_Eid5QZqqDSqGJm2DV8uxncbFsYPtDPrtcWg3tYgHlAdH9u8eX597suwlgnNESnS6dqO33MwHZ9UcQljlJX6UHaOa4BnFkDze-z_KnoWwhrAgFaVPsyMMYY5QgY-z71_OL_ACBG2UFdquAI9R2ZFHFYBxXM60laNQEhjVRnCnbPRajIZ70G0G5aN3Q7cBzQb0TqbtOEn0t1fXpzf0Mxh47H7yDdAW9Fqo59mTlpugXuzWk-zrxfnt4tPs8urjcnF2ORMlruOsqQmnLUo9tgRVTQNbygmVLedElQ1uEYdSIoyEynElKBUoLxvZlHnNG0hRQU6y11vdwbjAdj4FhnCNCayrciKWW0I6vmaD1z33G-a4Zn82nF8x7qMWRjEiqhZKlHyjVU6apqaqmjSkqnGe5zBpfdjdNja9kmKyiJsD0cMTqzu2cncMl3WeBpIE3u0EvPsxqhBZr4NQxnCr3BhYSdK4CS2mtt_8Rf77cfMtteKpf21bl64V6ZMqTSGlpU3DZmcpLmWBaFGngvcHBYmJ6ldc8TEEtry5_n_26tsh-3aP7RQ3sQvOjFE7Gw7BfAsK70Lwqn1wD0E2hf3-nWwKO9uFPZW92nf-oeg-3eQ3DCD6sQ</recordid><startdate>20091229</startdate><enddate>20091229</enddate><creator>Pereira, Ana Helena M</creator><creator>Clemente, Carolina F M Z</creator><creator>Cardoso, Alisson C</creator><creator>Theizen, Thais H</creator><creator>Rocco, Silvana A</creator><creator>Judice, Carla C</creator><creator>Guido, Maria Carolina</creator><creator>Pascoal, Vinícius D B</creator><creator>Lopes-Cendes, Iscia</creator><creator>Souza, José Roberto M</creator><creator>Franchini, Kleber G</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>AEUYN</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>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20091229</creationdate><title>MEF2C silencing attenuates load-induced left ventricular hypertrophy by modulating mTOR/S6K pathway in mice</title><author>Pereira, Ana Helena M ; Clemente, Carolina F M Z ; Cardoso, Alisson C ; Theizen, Thais H ; Rocco, Silvana A ; Judice, Carla C ; Guido, Maria Carolina ; Pascoal, Vinícius D B ; Lopes-Cendes, Iscia ; Souza, José Roberto M ; Franchini, Kleber G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c729t-b93a6f1200f318bb0f6a36dfaa3e7b2f1a0dd121ce428c66c147bdb749ab06153</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Activation</topic><topic>Amino acids</topic><topic>AMP</topic><topic>Animals</topic><topic>Aorta</topic><topic>Atherosclerosis</topic><topic>Attenuation</topic><topic>Biochemistry/Cell Signaling and Trafficking Structures</topic><topic>Biochemistry/Transcription and Translation</topic><topic>Biosynthesis</topic><topic>Cardiomyocytes</topic><topic>Cardiomyopathy</topic><topic>Cardiovascular Disorders/Heart Failure</topic><topic>Cell Biology/Cell Growth and Division</topic><topic>Cell growth</topic><topic>Cells, Cultured</topic><topic>Deoxyribonucleic acid</topic><topic>Depletion</topic><topic>DNA</topic><topic>DNA binding proteins</topic><topic>DNA, Mitochondrial - genetics</topic><topic>Fibrosis</topic><topic>Gene Silencing</topic><topic>Heart</topic><topic>Heart diseases</topic><topic>Heart failure</topic><topic>Heart hypertrophy</topic><topic>Hemodynamics</topic><topic>Hypertrophy</topic><topic>Hypertrophy, Left Ventricular - enzymology</topic><topic>Hypertrophy, Left Ventricular - physiopathology</topic><topic>Internal medicine</topic><topic>Intracellular Signaling Peptides and Proteins - metabolism</topic><topic>Kinases</topic><topic>Leucine</topic><topic>Medicine</topic><topic>MEF2 Transcription Factors</topic><topic>Mice</topic><topic>Mitochondrial DNA</topic><topic>Myocardium - enzymology</topic><topic>Myocardium - pathology</topic><topic>Myocytes, Cardiac - metabolism</topic><topic>Myocytes, Cardiac - pathology</topic><topic>Myogenic Regulatory Factors - genetics</topic><topic>Myogenic Regulatory Factors - metabolism</topic><topic>Pathogenesis</topic><topic>Pressure</topic><topic>Protein expression</topic><topic>Protein synthesis</topic><topic>Protein-Serine-Threonine Kinases - 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However, the role of its individual components in the pathogenesis of cardiac hypertrophy remains unclear.
In this study, we investigated whether MEF2C plays a role in mediating the left ventricular hypertrophy by pressure overload in mice. The knockdown of myocardial MEF2C induced by specific small interfering RNA (siRNA) has been shown to attenuate hypertrophy, interstitial fibrosis and the rise of ANP levels in aortic banded mice. We detected that the depletion of MEF2C also results in lowered levels of both PGC-1alpha and mitochondrial DNA in the overloaded left ventricle, associated with enhanced AMP:ATP ratio. Additionally, MEF2C depletion was accompanied by defective activation of S6K in response to pressure overload. Treatment with the amino acid leucine stimulated S6K and suppressed the attenuation of left ventricular hypertrophy and fibrosis in the aforementioned aortic banded mice.
These findings represent new evidences that MEF2C depletion attenuates the hypertrophic responses to mechanical stress and highlight the potential of MEF2C to be a target for new therapies to cardiac hypertrophy and failure.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>20041152</pmid><doi>10.1371/journal.pone.0008472</doi><tpages>e8472</tpages><oa>free_for_read</oa></addata></record> |
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source | MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
subjects | Activation Amino acids AMP Animals Aorta Atherosclerosis Attenuation Biochemistry/Cell Signaling and Trafficking Structures Biochemistry/Transcription and Translation Biosynthesis Cardiomyocytes Cardiomyopathy Cardiovascular Disorders/Heart Failure Cell Biology/Cell Growth and Division Cell growth Cells, Cultured Deoxyribonucleic acid Depletion DNA DNA binding proteins DNA, Mitochondrial - genetics Fibrosis Gene Silencing Heart Heart diseases Heart failure Heart hypertrophy Hemodynamics Hypertrophy Hypertrophy, Left Ventricular - enzymology Hypertrophy, Left Ventricular - physiopathology Internal medicine Intracellular Signaling Peptides and Proteins - metabolism Kinases Leucine Medicine MEF2 Transcription Factors Mice Mitochondrial DNA Myocardium - enzymology Myocardium - pathology Myocytes, Cardiac - metabolism Myocytes, Cardiac - pathology Myogenic Regulatory Factors - genetics Myogenic Regulatory Factors - metabolism Pathogenesis Pressure Protein expression Protein synthesis Protein-Serine-Threonine Kinases - metabolism Proteins Rats Ribonucleic acid Ribosomal Protein S6 Kinases, 90-kDa - metabolism RNA RNA, Small Interfering - metabolism Rodents Signal Transduction siRNA Stem cells TOR protein TOR Serine-Threonine Kinases Transcription factors Ventricle Ventricular Pressure - physiology |
title | MEF2C silencing attenuates load-induced left ventricular hypertrophy by modulating mTOR/S6K pathway in mice |
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