Estrogen-related receptor gamma induces cardiac hypertrophy by activating GATA4
Abstract Estrogen-related receptor gamma (ERRγ) is an orphan nuclear receptor that has biological roles mainly in metabolism and that controls metabolic switching in perinatal heart. In adult heart diseases, however, the functional roles of ERRγ have not yet been elucidated. In the present study, we...
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| Veröffentlicht in: | Journal of molecular and cellular cardiology 2013-12, Vol.65, p.88-97 |
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| creator | Kwon, Duk-Hwa Eom, Gwang Hyeon Kee, Hae Jin Nam, Yoon Seok Cho, Young Kuk Kim, Don-Kyu Koo, Ja Young Kim, Hyung-Seok Nam, Kwang-Il Kim, Kyung Keun Lee, In-Kyu Park, Seung Bum Choi, Hueng-Sik Kook, Hyun |
| description | Abstract Estrogen-related receptor gamma (ERRγ) is an orphan nuclear receptor that has biological roles mainly in metabolism and that controls metabolic switching in perinatal heart. In adult heart diseases, however, the functional roles of ERRγ have not yet been elucidated. In the present study, we aimed to characterize the role of ERRγ in cardiac hypertrophy. The functional roles of ERRγ in the development of cardiac hypertrophy were examined in primary cultured cardiomyocytes and in animal models. ERRγ expression was increased in hearts from human hypertrophic cardiomyopathy patients and in both cellular and animal models of cardiac hypertrophy. Transgenic overexpression in mouse heart as well as forced expression of ERRγ in cardiomyocytes induced hypertrophic phenotypes. Knock-down of ERRγ blocked agonist-induced hypertrophic phenotypes. ERRγ bound directly to the proximal ERR-responsive element in the GATA4 promoter in a sequence-specific manner and thereby induced transcription. ERRγ-induced hypertrophy was blocked by inhibition of GATA4. GSK-5182, an inverse agonist of ERRγ, completely blocked cardiac hypertrophy in cardiomyocytes. It also prevented aortic banding-induced cardiac hypertrophy and fibrosis in mouse heart. These findings demonstrate a novel ERRγ/GATA4 signal cascade in the development of cardiac hypertrophy and suggest GSK-5182 as a possible therapeutic. |
| doi_str_mv | 10.1016/j.yjmcc.2013.09.011 |
| format | Article |
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In adult heart diseases, however, the functional roles of ERRγ have not yet been elucidated. In the present study, we aimed to characterize the role of ERRγ in cardiac hypertrophy. The functional roles of ERRγ in the development of cardiac hypertrophy were examined in primary cultured cardiomyocytes and in animal models. ERRγ expression was increased in hearts from human hypertrophic cardiomyopathy patients and in both cellular and animal models of cardiac hypertrophy. Transgenic overexpression in mouse heart as well as forced expression of ERRγ in cardiomyocytes induced hypertrophic phenotypes. Knock-down of ERRγ blocked agonist-induced hypertrophic phenotypes. ERRγ bound directly to the proximal ERR-responsive element in the GATA4 promoter in a sequence-specific manner and thereby induced transcription. ERRγ-induced hypertrophy was blocked by inhibition of GATA4. GSK-5182, an inverse agonist of ERRγ, completely blocked cardiac hypertrophy in cardiomyocytes. It also prevented aortic banding-induced cardiac hypertrophy and fibrosis in mouse heart. These findings demonstrate a novel ERRγ/GATA4 signal cascade in the development of cardiac hypertrophy and suggest GSK-5182 as a possible therapeutic.</description><identifier>ISSN: 0022-2828</identifier><identifier>EISSN: 1095-8584</identifier><identifier>DOI: 10.1016/j.yjmcc.2013.09.011</identifier><identifier>PMID: 24083978</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Adult ; Animals ; Atrial Natriuretic Factor - metabolism ; Base Sequence ; Cardiac hypertrophy ; Cardiomegaly - genetics ; Cardiomegaly - pathology ; Cardiovascular ; Drug Inverse Agonism ; Estrogen-related receptor gamma ; GATA4 ; GATA4 Transcription Factor - genetics ; GATA4 Transcription Factor - metabolism ; Gene Knockdown Techniques ; GSK-5182 ; Humans ; Mice ; Mice, Inbred C57BL ; Molecular Sequence Data ; Myocytes, Cardiac - drug effects ; Myocytes, Cardiac - metabolism ; Myocytes, Cardiac - pathology ; Orphan nuclear receptor ; Phenotype ; Protein Binding - drug effects ; Protein Binding - genetics ; Receptors, Estrogen - genetics ; Receptors, Estrogen - metabolism ; Response Elements - genetics ; Tamoxifen - analogs & derivatives ; Tamoxifen - pharmacology ; Transcriptional Activation - drug effects ; Transcriptional Activation - genetics</subject><ispartof>Journal of molecular and cellular cardiology, 2013-12, Vol.65, p.88-97</ispartof><rights>Elsevier Ltd</rights><rights>2013 Elsevier Ltd</rights><rights>2013 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c414t-35fed491eeac3a32d8ee8e4b48083ba848c69f8e4bb8ab34842c4068acd12c003</citedby><cites>FETCH-LOGICAL-c414t-35fed491eeac3a32d8ee8e4b48083ba848c69f8e4bb8ab34842c4068acd12c003</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.yjmcc.2013.09.011$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24083978$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kwon, Duk-Hwa</creatorcontrib><creatorcontrib>Eom, Gwang Hyeon</creatorcontrib><creatorcontrib>Kee, Hae Jin</creatorcontrib><creatorcontrib>Nam, Yoon Seok</creatorcontrib><creatorcontrib>Cho, Young Kuk</creatorcontrib><creatorcontrib>Kim, Don-Kyu</creatorcontrib><creatorcontrib>Koo, Ja Young</creatorcontrib><creatorcontrib>Kim, Hyung-Seok</creatorcontrib><creatorcontrib>Nam, Kwang-Il</creatorcontrib><creatorcontrib>Kim, Kyung Keun</creatorcontrib><creatorcontrib>Lee, In-Kyu</creatorcontrib><creatorcontrib>Park, Seung Bum</creatorcontrib><creatorcontrib>Choi, Hueng-Sik</creatorcontrib><creatorcontrib>Kook, Hyun</creatorcontrib><title>Estrogen-related receptor gamma induces cardiac hypertrophy by activating GATA4</title><title>Journal of molecular and cellular cardiology</title><addtitle>J Mol Cell Cardiol</addtitle><description>Abstract Estrogen-related receptor gamma (ERRγ) is an orphan nuclear receptor that has biological roles mainly in metabolism and that controls metabolic switching in perinatal heart. In adult heart diseases, however, the functional roles of ERRγ have not yet been elucidated. In the present study, we aimed to characterize the role of ERRγ in cardiac hypertrophy. The functional roles of ERRγ in the development of cardiac hypertrophy were examined in primary cultured cardiomyocytes and in animal models. ERRγ expression was increased in hearts from human hypertrophic cardiomyopathy patients and in both cellular and animal models of cardiac hypertrophy. Transgenic overexpression in mouse heart as well as forced expression of ERRγ in cardiomyocytes induced hypertrophic phenotypes. Knock-down of ERRγ blocked agonist-induced hypertrophic phenotypes. ERRγ bound directly to the proximal ERR-responsive element in the GATA4 promoter in a sequence-specific manner and thereby induced transcription. ERRγ-induced hypertrophy was blocked by inhibition of GATA4. GSK-5182, an inverse agonist of ERRγ, completely blocked cardiac hypertrophy in cardiomyocytes. It also prevented aortic banding-induced cardiac hypertrophy and fibrosis in mouse heart. These findings demonstrate a novel ERRγ/GATA4 signal cascade in the development of cardiac hypertrophy and suggest GSK-5182 as a possible therapeutic.</description><subject>Adult</subject><subject>Animals</subject><subject>Atrial Natriuretic Factor - metabolism</subject><subject>Base Sequence</subject><subject>Cardiac hypertrophy</subject><subject>Cardiomegaly - genetics</subject><subject>Cardiomegaly - pathology</subject><subject>Cardiovascular</subject><subject>Drug Inverse Agonism</subject><subject>Estrogen-related receptor gamma</subject><subject>GATA4</subject><subject>GATA4 Transcription Factor - genetics</subject><subject>GATA4 Transcription Factor - metabolism</subject><subject>Gene Knockdown Techniques</subject><subject>GSK-5182</subject><subject>Humans</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Molecular Sequence Data</subject><subject>Myocytes, Cardiac - drug effects</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>Myocytes, Cardiac - pathology</subject><subject>Orphan nuclear receptor</subject><subject>Phenotype</subject><subject>Protein Binding - drug effects</subject><subject>Protein Binding - genetics</subject><subject>Receptors, Estrogen - genetics</subject><subject>Receptors, Estrogen - metabolism</subject><subject>Response Elements - genetics</subject><subject>Tamoxifen - analogs & derivatives</subject><subject>Tamoxifen - pharmacology</subject><subject>Transcriptional Activation - drug effects</subject><subject>Transcriptional Activation - genetics</subject><issn>0022-2828</issn><issn>1095-8584</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU1v1DAQhi1ERbeFX4CEcuSSMP7I1jmAtKpKW6lSDy1nyxnPbh3yhZ1Uyr_H6RYOXDjNaPS-8_EMYx85FBz49ktTLE2HWAjgsoCqAM7fsA2Hqsx1qdVbtgEQIhda6FN2FmMDAJWS8h07FQq0rC70ht1fxSkMB-rzQK2dyGWBkMZpCNnBdp3NfO9mpJihDc5bzJ6WkUKyjE9LVi-Zxck_28n3h-x697hT79nJ3raRPrzGc_bj-9Xj5U1-d399e7m7y1FxNeWy3JNTFSeyKK0UThNpUrXSabHaaqVxW-3XSq1tLZVWAhVstUXHBQLIc_b52HcMw6-Z4mQ6H5Ha1vY0zNFwVVbpwKrUSSqPUgxDjIH2Zgy-s2ExHMxK0jTmhaRZSRqoTCKZXJ9eB8x1R-6v5w-6JPh6FFA689lTMBE99UjOJ4STcYP_z4Bv__ix9b1H2_6khWIzzKFPBA03URgwD-sz119ymbILVcrfYKma1w</recordid><startdate>20131201</startdate><enddate>20131201</enddate><creator>Kwon, Duk-Hwa</creator><creator>Eom, Gwang Hyeon</creator><creator>Kee, Hae Jin</creator><creator>Nam, Yoon Seok</creator><creator>Cho, Young Kuk</creator><creator>Kim, Don-Kyu</creator><creator>Koo, Ja Young</creator><creator>Kim, Hyung-Seok</creator><creator>Nam, Kwang-Il</creator><creator>Kim, Kyung Keun</creator><creator>Lee, In-Kyu</creator><creator>Park, Seung Bum</creator><creator>Choi, Hueng-Sik</creator><creator>Kook, Hyun</creator><general>Elsevier Ltd</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>7X8</scope></search><sort><creationdate>20131201</creationdate><title>Estrogen-related receptor gamma induces cardiac hypertrophy by activating GATA4</title><author>Kwon, Duk-Hwa ; Eom, Gwang Hyeon ; Kee, Hae Jin ; Nam, Yoon Seok ; Cho, Young Kuk ; Kim, Don-Kyu ; Koo, Ja Young ; Kim, Hyung-Seok ; Nam, Kwang-Il ; Kim, Kyung Keun ; Lee, In-Kyu ; Park, Seung Bum ; Choi, Hueng-Sik ; Kook, Hyun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c414t-35fed491eeac3a32d8ee8e4b48083ba848c69f8e4bb8ab34842c4068acd12c003</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Adult</topic><topic>Animals</topic><topic>Atrial Natriuretic Factor - metabolism</topic><topic>Base Sequence</topic><topic>Cardiac hypertrophy</topic><topic>Cardiomegaly - genetics</topic><topic>Cardiomegaly - pathology</topic><topic>Cardiovascular</topic><topic>Drug Inverse Agonism</topic><topic>Estrogen-related receptor gamma</topic><topic>GATA4</topic><topic>GATA4 Transcription Factor - genetics</topic><topic>GATA4 Transcription Factor - metabolism</topic><topic>Gene Knockdown Techniques</topic><topic>GSK-5182</topic><topic>Humans</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Molecular Sequence Data</topic><topic>Myocytes, Cardiac - drug effects</topic><topic>Myocytes, Cardiac - metabolism</topic><topic>Myocytes, Cardiac - pathology</topic><topic>Orphan nuclear receptor</topic><topic>Phenotype</topic><topic>Protein Binding - drug effects</topic><topic>Protein Binding - genetics</topic><topic>Receptors, Estrogen - genetics</topic><topic>Receptors, Estrogen - metabolism</topic><topic>Response Elements - genetics</topic><topic>Tamoxifen - analogs & derivatives</topic><topic>Tamoxifen - pharmacology</topic><topic>Transcriptional Activation - drug effects</topic><topic>Transcriptional Activation - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kwon, Duk-Hwa</creatorcontrib><creatorcontrib>Eom, Gwang Hyeon</creatorcontrib><creatorcontrib>Kee, Hae Jin</creatorcontrib><creatorcontrib>Nam, Yoon Seok</creatorcontrib><creatorcontrib>Cho, Young Kuk</creatorcontrib><creatorcontrib>Kim, Don-Kyu</creatorcontrib><creatorcontrib>Koo, Ja Young</creatorcontrib><creatorcontrib>Kim, Hyung-Seok</creatorcontrib><creatorcontrib>Nam, Kwang-Il</creatorcontrib><creatorcontrib>Kim, Kyung Keun</creatorcontrib><creatorcontrib>Lee, In-Kyu</creatorcontrib><creatorcontrib>Park, Seung Bum</creatorcontrib><creatorcontrib>Choi, Hueng-Sik</creatorcontrib><creatorcontrib>Kook, Hyun</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of molecular and cellular cardiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kwon, Duk-Hwa</au><au>Eom, Gwang Hyeon</au><au>Kee, Hae Jin</au><au>Nam, Yoon Seok</au><au>Cho, Young Kuk</au><au>Kim, Don-Kyu</au><au>Koo, Ja Young</au><au>Kim, Hyung-Seok</au><au>Nam, Kwang-Il</au><au>Kim, Kyung Keun</au><au>Lee, In-Kyu</au><au>Park, Seung Bum</au><au>Choi, Hueng-Sik</au><au>Kook, Hyun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Estrogen-related receptor gamma induces cardiac hypertrophy by activating GATA4</atitle><jtitle>Journal of molecular and cellular cardiology</jtitle><addtitle>J Mol Cell Cardiol</addtitle><date>2013-12-01</date><risdate>2013</risdate><volume>65</volume><spage>88</spage><epage>97</epage><pages>88-97</pages><issn>0022-2828</issn><eissn>1095-8584</eissn><abstract>Abstract Estrogen-related receptor gamma (ERRγ) is an orphan nuclear receptor that has biological roles mainly in metabolism and that controls metabolic switching in perinatal heart. In adult heart diseases, however, the functional roles of ERRγ have not yet been elucidated. In the present study, we aimed to characterize the role of ERRγ in cardiac hypertrophy. The functional roles of ERRγ in the development of cardiac hypertrophy were examined in primary cultured cardiomyocytes and in animal models. ERRγ expression was increased in hearts from human hypertrophic cardiomyopathy patients and in both cellular and animal models of cardiac hypertrophy. Transgenic overexpression in mouse heart as well as forced expression of ERRγ in cardiomyocytes induced hypertrophic phenotypes. Knock-down of ERRγ blocked agonist-induced hypertrophic phenotypes. ERRγ bound directly to the proximal ERR-responsive element in the GATA4 promoter in a sequence-specific manner and thereby induced transcription. ERRγ-induced hypertrophy was blocked by inhibition of GATA4. GSK-5182, an inverse agonist of ERRγ, completely blocked cardiac hypertrophy in cardiomyocytes. It also prevented aortic banding-induced cardiac hypertrophy and fibrosis in mouse heart. These findings demonstrate a novel ERRγ/GATA4 signal cascade in the development of cardiac hypertrophy and suggest GSK-5182 as a possible therapeutic.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>24083978</pmid><doi>10.1016/j.yjmcc.2013.09.011</doi><tpages>10</tpages></addata></record> |
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| subjects | Adult Animals Atrial Natriuretic Factor - metabolism Base Sequence Cardiac hypertrophy Cardiomegaly - genetics Cardiomegaly - pathology Cardiovascular Drug Inverse Agonism Estrogen-related receptor gamma GATA4 GATA4 Transcription Factor - genetics GATA4 Transcription Factor - metabolism Gene Knockdown Techniques GSK-5182 Humans Mice Mice, Inbred C57BL Molecular Sequence Data Myocytes, Cardiac - drug effects Myocytes, Cardiac - metabolism Myocytes, Cardiac - pathology Orphan nuclear receptor Phenotype Protein Binding - drug effects Protein Binding - genetics Receptors, Estrogen - genetics Receptors, Estrogen - metabolism Response Elements - genetics Tamoxifen - analogs & derivatives Tamoxifen - pharmacology Transcriptional Activation - drug effects Transcriptional Activation - genetics |
| title | Estrogen-related receptor gamma induces cardiac hypertrophy by activating GATA4 |
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