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Reversal of pathological cardiac hypertrophy via the MEF2-coregulator interface
Cardiac hypertrophy, as a response to hemodynamic stress, is associated with cardiac dysfunction and death, but whether hypertrophy itself represents a pathological process remains unclear. Hypertrophy is driven by changes in myocardial gene expression that require the MEF2 family of DNA-binding tra...
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| Published in: | JCI insight 2017-09, Vol.2 (17) |
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| creator | Wei, Jianqin Joshi, Shaurya Speransky, Svetlana Crowley, Christopher Jayathilaka, Nimanthi Lei, Xiao Wu, Yongqing Gai, David Jain, Sumit Hoosien, Michael Gao, Yan Chen, Lin Bishopric, Nanette H |
| description | Cardiac hypertrophy, as a response to hemodynamic stress, is associated with cardiac dysfunction and death, but whether hypertrophy itself represents a pathological process remains unclear. Hypertrophy is driven by changes in myocardial gene expression that require the MEF2 family of DNA-binding transcription factors, as well as the nuclear lysine acetyltransferase p300. Here we used genetic and small-molecule probes to determine the effects of preventing MEF2 acetylation on cardiac adaptation to stress. Both nonacetylatable MEF2 mutants and 8MI, a molecule designed to interfere with MEF2-coregulator binding, prevented hypertrophy in cultured cardiac myocytes. 8MI prevented cardiac hypertrophy in 3 distinct stress models, and reversed established hypertrophy in vivo, associated with normalization of myocardial structure and function. The effects of 8MI were reversible, and did not prevent training effects of swimming. Mechanistically, 8MI blocked stress-induced MEF2 acetylation, nuclear export of class II histone deacetylases HDAC4 and -5, and p300 induction, without impeding HDAC4 phosphorylation. Correspondingly, 8MI transformed the transcriptional response to pressure overload, normalizing almost all 232 genes dysregulated by hemodynamic stress. We conclude that MEF2 acetylation is required for development and maintenance of pathological cardiac hypertrophy, and that blocking MEF2 acetylation can permit recovery from hypertrophy without impairing physiologic adaptation. |
| doi_str_mv | 10.1172/jci.insight.91068 |
| format | article |
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Hypertrophy is driven by changes in myocardial gene expression that require the MEF2 family of DNA-binding transcription factors, as well as the nuclear lysine acetyltransferase p300. Here we used genetic and small-molecule probes to determine the effects of preventing MEF2 acetylation on cardiac adaptation to stress. Both nonacetylatable MEF2 mutants and 8MI, a molecule designed to interfere with MEF2-coregulator binding, prevented hypertrophy in cultured cardiac myocytes. 8MI prevented cardiac hypertrophy in 3 distinct stress models, and reversed established hypertrophy in vivo, associated with normalization of myocardial structure and function. The effects of 8MI were reversible, and did not prevent training effects of swimming. Mechanistically, 8MI blocked stress-induced MEF2 acetylation, nuclear export of class II histone deacetylases HDAC4 and -5, and p300 induction, without impeding HDAC4 phosphorylation. Correspondingly, 8MI transformed the transcriptional response to pressure overload, normalizing almost all 232 genes dysregulated by hemodynamic stress. We conclude that MEF2 acetylation is required for development and maintenance of pathological cardiac hypertrophy, and that blocking MEF2 acetylation can permit recovery from hypertrophy without impairing physiologic adaptation.</description><identifier>ISSN: 2379-3708</identifier><identifier>EISSN: 2379-3708</identifier><identifier>DOI: 10.1172/jci.insight.91068</identifier><identifier>PMID: 28878124</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Acetylation ; Animals ; Cardiomegaly - genetics ; Cardiomegaly - metabolism ; Cardiomegaly - physiopathology ; Cardiomegaly - prevention & control ; Cells, Cultured ; Histone Deacetylase Inhibitors - pharmacology ; Histone Deacetylases - metabolism ; Humans ; MEF2 Transcription Factors - antagonists & inhibitors ; MEF2 Transcription Factors - metabolism ; Mice ; Myocardial Contraction ; p300-CBP Transcription Factors - biosynthesis ; Phosphorylation ; Protein Binding ; Protein Transport ; Rats ; Repressor Proteins - metabolism ; Stress, Physiological ; Transcription, Genetic</subject><ispartof>JCI insight, 2017-09, Vol.2 (17)</ispartof><rights>Copyright © 2017, American Society for Clinical Investigation 2017 American Society for Clinical Investigation</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c465t-1c22d81389a86e9dd417c13b7cd7f734e2fa528a009b9b9e809322c195723d993</citedby><cites>FETCH-LOGICAL-c465t-1c22d81389a86e9dd417c13b7cd7f734e2fa528a009b9b9e809322c195723d993</cites><orcidid>0000-0003-4798-6199 ; 0000-0002-8398-5997</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5621875/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5621875/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,315,733,786,790,891,27957,27958,53827,53829</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28878124$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wei, Jianqin</creatorcontrib><creatorcontrib>Joshi, Shaurya</creatorcontrib><creatorcontrib>Speransky, Svetlana</creatorcontrib><creatorcontrib>Crowley, Christopher</creatorcontrib><creatorcontrib>Jayathilaka, Nimanthi</creatorcontrib><creatorcontrib>Lei, Xiao</creatorcontrib><creatorcontrib>Wu, Yongqing</creatorcontrib><creatorcontrib>Gai, David</creatorcontrib><creatorcontrib>Jain, Sumit</creatorcontrib><creatorcontrib>Hoosien, Michael</creatorcontrib><creatorcontrib>Gao, Yan</creatorcontrib><creatorcontrib>Chen, Lin</creatorcontrib><creatorcontrib>Bishopric, Nanette H</creatorcontrib><title>Reversal of pathological cardiac hypertrophy via the MEF2-coregulator interface</title><title>JCI insight</title><addtitle>JCI Insight</addtitle><description>Cardiac hypertrophy, as a response to hemodynamic stress, is associated with cardiac dysfunction and death, but whether hypertrophy itself represents a pathological process remains unclear. Hypertrophy is driven by changes in myocardial gene expression that require the MEF2 family of DNA-binding transcription factors, as well as the nuclear lysine acetyltransferase p300. Here we used genetic and small-molecule probes to determine the effects of preventing MEF2 acetylation on cardiac adaptation to stress. Both nonacetylatable MEF2 mutants and 8MI, a molecule designed to interfere with MEF2-coregulator binding, prevented hypertrophy in cultured cardiac myocytes. 8MI prevented cardiac hypertrophy in 3 distinct stress models, and reversed established hypertrophy in vivo, associated with normalization of myocardial structure and function. The effects of 8MI were reversible, and did not prevent training effects of swimming. Mechanistically, 8MI blocked stress-induced MEF2 acetylation, nuclear export of class II histone deacetylases HDAC4 and -5, and p300 induction, without impeding HDAC4 phosphorylation. Correspondingly, 8MI transformed the transcriptional response to pressure overload, normalizing almost all 232 genes dysregulated by hemodynamic stress. We conclude that MEF2 acetylation is required for development and maintenance of pathological cardiac hypertrophy, and that blocking MEF2 acetylation can permit recovery from hypertrophy without impairing physiologic adaptation.</description><subject>Acetylation</subject><subject>Animals</subject><subject>Cardiomegaly - genetics</subject><subject>Cardiomegaly - metabolism</subject><subject>Cardiomegaly - physiopathology</subject><subject>Cardiomegaly - prevention & control</subject><subject>Cells, Cultured</subject><subject>Histone Deacetylase Inhibitors - pharmacology</subject><subject>Histone Deacetylases - metabolism</subject><subject>Humans</subject><subject>MEF2 Transcription Factors - antagonists & inhibitors</subject><subject>MEF2 Transcription Factors - metabolism</subject><subject>Mice</subject><subject>Myocardial Contraction</subject><subject>p300-CBP Transcription Factors - biosynthesis</subject><subject>Phosphorylation</subject><subject>Protein Binding</subject><subject>Protein Transport</subject><subject>Rats</subject><subject>Repressor Proteins - metabolism</subject><subject>Stress, Physiological</subject><subject>Transcription, Genetic</subject><issn>2379-3708</issn><issn>2379-3708</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><recordid>eNpVUcFKxDAQDaKo6H6AF-nRS9dk0jbJRRBxVVAWRM8hm063kW5Tk-zC_r1VV1HmMDPMe2-GeYScMTplTMDlm3VT10e3bNNUMVrJPXIMXKicCyr3_9RHZBLjG6WUiQJoKQ_JEUgpJIPimMyfcYMhmi7zTTaY1PrOL50de2tC7YzN2u2AIQU_tNts40yWWsyebmeQWx9wue5M8iFzfcLQGIun5KAxXcTJLp-Q19nty819_ji_e7i5fsxtUZUpZxagloxLZWSFqq4LJizjC2Fr0QheIDSmBGkoVYsxUFLFASxTpQBeK8VPyNW37rBerLC22KdgOj0EtzJhq71x-v-kd61e-o0uK2BSlKPAxU4g-Pc1xqRXLlrsOtOjX0fNFK8qACjoCGXfUBt8jAGb3zWM6k8v9OiF3nmhv7wYOed_7_tl_HyefwDq5IkM</recordid><startdate>20170907</startdate><enddate>20170907</enddate><creator>Wei, Jianqin</creator><creator>Joshi, Shaurya</creator><creator>Speransky, Svetlana</creator><creator>Crowley, Christopher</creator><creator>Jayathilaka, Nimanthi</creator><creator>Lei, Xiao</creator><creator>Wu, Yongqing</creator><creator>Gai, David</creator><creator>Jain, Sumit</creator><creator>Hoosien, Michael</creator><creator>Gao, Yan</creator><creator>Chen, Lin</creator><creator>Bishopric, Nanette H</creator><general>American Society for Clinical Investigation</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><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-4798-6199</orcidid><orcidid>https://orcid.org/0000-0002-8398-5997</orcidid></search><sort><creationdate>20170907</creationdate><title>Reversal of pathological cardiac hypertrophy via the MEF2-coregulator interface</title><author>Wei, Jianqin ; Joshi, Shaurya ; Speransky, Svetlana ; Crowley, Christopher ; Jayathilaka, Nimanthi ; Lei, Xiao ; Wu, Yongqing ; Gai, David ; Jain, Sumit ; Hoosien, Michael ; Gao, Yan ; Chen, Lin ; Bishopric, Nanette H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c465t-1c22d81389a86e9dd417c13b7cd7f734e2fa528a009b9b9e809322c195723d993</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Acetylation</topic><topic>Animals</topic><topic>Cardiomegaly - genetics</topic><topic>Cardiomegaly - metabolism</topic><topic>Cardiomegaly - physiopathology</topic><topic>Cardiomegaly - prevention & control</topic><topic>Cells, Cultured</topic><topic>Histone Deacetylase Inhibitors - pharmacology</topic><topic>Histone Deacetylases - metabolism</topic><topic>Humans</topic><topic>MEF2 Transcription Factors - antagonists & inhibitors</topic><topic>MEF2 Transcription Factors - metabolism</topic><topic>Mice</topic><topic>Myocardial Contraction</topic><topic>p300-CBP Transcription Factors - biosynthesis</topic><topic>Phosphorylation</topic><topic>Protein Binding</topic><topic>Protein Transport</topic><topic>Rats</topic><topic>Repressor Proteins - metabolism</topic><topic>Stress, Physiological</topic><topic>Transcription, Genetic</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wei, Jianqin</creatorcontrib><creatorcontrib>Joshi, Shaurya</creatorcontrib><creatorcontrib>Speransky, Svetlana</creatorcontrib><creatorcontrib>Crowley, Christopher</creatorcontrib><creatorcontrib>Jayathilaka, Nimanthi</creatorcontrib><creatorcontrib>Lei, Xiao</creatorcontrib><creatorcontrib>Wu, Yongqing</creatorcontrib><creatorcontrib>Gai, David</creatorcontrib><creatorcontrib>Jain, Sumit</creatorcontrib><creatorcontrib>Hoosien, Michael</creatorcontrib><creatorcontrib>Gao, Yan</creatorcontrib><creatorcontrib>Chen, Lin</creatorcontrib><creatorcontrib>Bishopric, Nanette H</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><collection>PubMed Central (Full Participant titles)</collection><jtitle>JCI insight</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wei, Jianqin</au><au>Joshi, Shaurya</au><au>Speransky, Svetlana</au><au>Crowley, Christopher</au><au>Jayathilaka, Nimanthi</au><au>Lei, Xiao</au><au>Wu, Yongqing</au><au>Gai, David</au><au>Jain, Sumit</au><au>Hoosien, Michael</au><au>Gao, Yan</au><au>Chen, Lin</au><au>Bishopric, Nanette H</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Reversal of pathological cardiac hypertrophy via the MEF2-coregulator interface</atitle><jtitle>JCI insight</jtitle><addtitle>JCI Insight</addtitle><date>2017-09-07</date><risdate>2017</risdate><volume>2</volume><issue>17</issue><issn>2379-3708</issn><eissn>2379-3708</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><notes>Authorship note: J. Wei and S. Joshi contributed equally to this work.</notes><abstract>Cardiac hypertrophy, as a response to hemodynamic stress, is associated with cardiac dysfunction and death, but whether hypertrophy itself represents a pathological process remains unclear. Hypertrophy is driven by changes in myocardial gene expression that require the MEF2 family of DNA-binding transcription factors, as well as the nuclear lysine acetyltransferase p300. Here we used genetic and small-molecule probes to determine the effects of preventing MEF2 acetylation on cardiac adaptation to stress. Both nonacetylatable MEF2 mutants and 8MI, a molecule designed to interfere with MEF2-coregulator binding, prevented hypertrophy in cultured cardiac myocytes. 8MI prevented cardiac hypertrophy in 3 distinct stress models, and reversed established hypertrophy in vivo, associated with normalization of myocardial structure and function. The effects of 8MI were reversible, and did not prevent training effects of swimming. Mechanistically, 8MI blocked stress-induced MEF2 acetylation, nuclear export of class II histone deacetylases HDAC4 and -5, and p300 induction, without impeding HDAC4 phosphorylation. Correspondingly, 8MI transformed the transcriptional response to pressure overload, normalizing almost all 232 genes dysregulated by hemodynamic stress. We conclude that MEF2 acetylation is required for development and maintenance of pathological cardiac hypertrophy, and that blocking MEF2 acetylation can permit recovery from hypertrophy without impairing physiologic adaptation.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>28878124</pmid><doi>10.1172/jci.insight.91068</doi><orcidid>https://orcid.org/0000-0003-4798-6199</orcidid><orcidid>https://orcid.org/0000-0002-8398-5997</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Acetylation Animals Cardiomegaly - genetics Cardiomegaly - metabolism Cardiomegaly - physiopathology Cardiomegaly - prevention & control Cells, Cultured Histone Deacetylase Inhibitors - pharmacology Histone Deacetylases - metabolism Humans MEF2 Transcription Factors - antagonists & inhibitors MEF2 Transcription Factors - metabolism Mice Myocardial Contraction p300-CBP Transcription Factors - biosynthesis Phosphorylation Protein Binding Protein Transport Rats Repressor Proteins - metabolism Stress, Physiological Transcription, Genetic |
| title | Reversal of pathological cardiac hypertrophy via the MEF2-coregulator interface |
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