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Increased regulatory activity of the calcineurin/NFAT pathway in human heart failure
Background: Cardiac hypertrophy may initiate progression to a compromised cardiac function. While the clinical consequences of hypertrophy are well understood, only little is known about the underlying molecular pathways. As reported from animal experiments, the Ca2+‐calmodulin activated phosphatase...
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| Published in: | European journal of heart failure 2004-01, Vol.6 (1), p.3-9 |
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| container_title | European journal of heart failure |
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| creator | Diedrichs, Holger Chi, Mei Boelck, Birgit Mehlhorm, Uwe Schwinger, Robert H.G. |
| description | Background:
Cardiac hypertrophy may initiate progression to a compromised cardiac function. While the clinical consequences of hypertrophy are well understood, only little is known about the underlying molecular pathways. As reported from animal experiments, the Ca2+‐calmodulin activated phosphatase calcineurin and its downstream transcriptional effector NFAT have been implicated as transducers of the hypertrophic response.
Methods and results:
To study whether the calcineurin pathway is activated in human heart failure, we investigated samples of human left ventricular myocardium from patients with dilated (idiopathic) cardiomyopathy (DCM, NYHA IV, n=8) in comparison with non‐failing controls (NF, n=8). We not only analyzed the pathway by measuring the calcineurin activity, but also by determination of the protein expression of the calcineurin B subunit and additional key markers of the calcineurin signaling cascade (NFAT‐3, GATA‐4). Calcineurin enzymatic activity was increased by 80% in human dilated cardiomyopathy compared with non‐failing human hearts (135.424±11.69 and 83.484±1.81 nmol Pi/min per μl). This was in line with increased protein expression of calcineurin B in DCM (71.18+9.11 vs. 46.41±11.23 densitometric units (DU)/μg protein). In order to verify the activated calcineurin pathway as described in animal models, we compared the protein expression of NFAT‐3 in homogenates within nuclear extracts. In nuclear extracts the protein level of NFAT‐3 was increased in dilated cardiomyopathy compared with non‐failing myocardium (104.01±8.85 vs. 71.47±8.79 DU/μg protein). In contrast, in homogenates the expression of NFAT‐3 was higher in the non‐failing tissue indicating subcellular redistribution (19.56±3.36 vs. 25.84±3.16 DU/μg protein). The protein expression of GATA‐4 was increased in DCM (43.14±2.89 vs. 29.87±2.17 DU/μg protein).
Conclusions:
In human heart failure (DCM) the calcineurin signaling pathway is activated not only by an increased activity of calcineurin and expression of GATA‐4, but also by the shift from dephosphorylated NFAT‐3 to the nucleus indicating subcellular redistribution and regulatory activation. |
| doi_str_mv | 10.1016/j.ejheart.2003.07.007 |
| format | article |
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Cardiac hypertrophy may initiate progression to a compromised cardiac function. While the clinical consequences of hypertrophy are well understood, only little is known about the underlying molecular pathways. As reported from animal experiments, the Ca2+‐calmodulin activated phosphatase calcineurin and its downstream transcriptional effector NFAT have been implicated as transducers of the hypertrophic response.
Methods and results:
To study whether the calcineurin pathway is activated in human heart failure, we investigated samples of human left ventricular myocardium from patients with dilated (idiopathic) cardiomyopathy (DCM, NYHA IV, n=8) in comparison with non‐failing controls (NF, n=8). We not only analyzed the pathway by measuring the calcineurin activity, but also by determination of the protein expression of the calcineurin B subunit and additional key markers of the calcineurin signaling cascade (NFAT‐3, GATA‐4). Calcineurin enzymatic activity was increased by 80% in human dilated cardiomyopathy compared with non‐failing human hearts (135.424±11.69 and 83.484±1.81 nmol Pi/min per μl). This was in line with increased protein expression of calcineurin B in DCM (71.18+9.11 vs. 46.41±11.23 densitometric units (DU)/μg protein). In order to verify the activated calcineurin pathway as described in animal models, we compared the protein expression of NFAT‐3 in homogenates within nuclear extracts. In nuclear extracts the protein level of NFAT‐3 was increased in dilated cardiomyopathy compared with non‐failing myocardium (104.01±8.85 vs. 71.47±8.79 DU/μg protein). In contrast, in homogenates the expression of NFAT‐3 was higher in the non‐failing tissue indicating subcellular redistribution (19.56±3.36 vs. 25.84±3.16 DU/μg protein). The protein expression of GATA‐4 was increased in DCM (43.14±2.89 vs. 29.87±2.17 DU/μg protein).
Conclusions:
In human heart failure (DCM) the calcineurin signaling pathway is activated not only by an increased activity of calcineurin and expression of GATA‐4, but also by the shift from dephosphorylated NFAT‐3 to the nucleus indicating subcellular redistribution and regulatory activation.</description><identifier>ISSN: 1388-9842</identifier><identifier>EISSN: 1879-0844</identifier><identifier>DOI: 10.1016/j.ejheart.2003.07.007</identifier><identifier>PMID: 15012912</identifier><language>eng</language><publisher>England: Blackwell Publishing Ltd</publisher><subject>Adult ; Calcineurin ; Calcineurin - genetics ; Calcineurin - metabolism ; Cardiomyopathy ; Cardiomyopathy, Dilated - metabolism ; Cell Nucleus - metabolism ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; Female ; GATA-4 ; GATA4 Transcription Factor ; Heart failure ; Humans ; Hypertrophy ; Male ; Middle Aged ; Myocardium - metabolism ; NFAT-3 ; NFATC Transcription Factors ; Nuclear Proteins ; RNA, Messenger - genetics ; Signal Transduction - physiology ; Transcription Factors - genetics ; Transcription Factors - metabolism</subject><ispartof>European journal of heart failure, 2004-01, Vol.6 (1), p.3-9</ispartof><rights>Published on behalf of the European Society of Cardiology. All rights reserved. © 2004 the Authors</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4687-a1c5c33b3dd146f2a3fd1a27744031019254ca3405ac858806faa13ffe687cc13</citedby><cites>FETCH-LOGICAL-c4687-a1c5c33b3dd146f2a3fd1a27744031019254ca3405ac858806faa13ffe687cc13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1016%2Fj.ejheart.2003.07.007$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1016%2Fj.ejheart.2003.07.007$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>315,786,790,27957,27958,50923,51032</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15012912$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Diedrichs, Holger</creatorcontrib><creatorcontrib>Chi, Mei</creatorcontrib><creatorcontrib>Boelck, Birgit</creatorcontrib><creatorcontrib>Mehlhorm, Uwe</creatorcontrib><creatorcontrib>Schwinger, Robert H.G.</creatorcontrib><title>Increased regulatory activity of the calcineurin/NFAT pathway in human heart failure</title><title>European journal of heart failure</title><addtitle>European Journal of Heart Failure</addtitle><description>Background:
Cardiac hypertrophy may initiate progression to a compromised cardiac function. While the clinical consequences of hypertrophy are well understood, only little is known about the underlying molecular pathways. As reported from animal experiments, the Ca2+‐calmodulin activated phosphatase calcineurin and its downstream transcriptional effector NFAT have been implicated as transducers of the hypertrophic response.
Methods and results:
To study whether the calcineurin pathway is activated in human heart failure, we investigated samples of human left ventricular myocardium from patients with dilated (idiopathic) cardiomyopathy (DCM, NYHA IV, n=8) in comparison with non‐failing controls (NF, n=8). We not only analyzed the pathway by measuring the calcineurin activity, but also by determination of the protein expression of the calcineurin B subunit and additional key markers of the calcineurin signaling cascade (NFAT‐3, GATA‐4). Calcineurin enzymatic activity was increased by 80% in human dilated cardiomyopathy compared with non‐failing human hearts (135.424±11.69 and 83.484±1.81 nmol Pi/min per μl). This was in line with increased protein expression of calcineurin B in DCM (71.18+9.11 vs. 46.41±11.23 densitometric units (DU)/μg protein). In order to verify the activated calcineurin pathway as described in animal models, we compared the protein expression of NFAT‐3 in homogenates within nuclear extracts. In nuclear extracts the protein level of NFAT‐3 was increased in dilated cardiomyopathy compared with non‐failing myocardium (104.01±8.85 vs. 71.47±8.79 DU/μg protein). In contrast, in homogenates the expression of NFAT‐3 was higher in the non‐failing tissue indicating subcellular redistribution (19.56±3.36 vs. 25.84±3.16 DU/μg protein). The protein expression of GATA‐4 was increased in DCM (43.14±2.89 vs. 29.87±2.17 DU/μg protein).
Conclusions:
In human heart failure (DCM) the calcineurin signaling pathway is activated not only by an increased activity of calcineurin and expression of GATA‐4, but also by the shift from dephosphorylated NFAT‐3 to the nucleus indicating subcellular redistribution and regulatory activation.</description><subject>Adult</subject><subject>Calcineurin</subject><subject>Calcineurin - genetics</subject><subject>Calcineurin - metabolism</subject><subject>Cardiomyopathy</subject><subject>Cardiomyopathy, Dilated - metabolism</subject><subject>Cell Nucleus - metabolism</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Female</subject><subject>GATA-4</subject><subject>GATA4 Transcription Factor</subject><subject>Heart failure</subject><subject>Humans</subject><subject>Hypertrophy</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Myocardium - metabolism</subject><subject>NFAT-3</subject><subject>NFATC Transcription Factors</subject><subject>Nuclear Proteins</subject><subject>RNA, Messenger - genetics</subject><subject>Signal Transduction - physiology</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><issn>1388-9842</issn><issn>1879-0844</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><recordid>eNqNkE9v1DAQxS0EoqXwEUA-cUs6E9uxcyxVt39UFQkttDdr6jisl2yy2Akl375Z7QrEjcvMHN57M_Nj7D1CjoDl6Tr365WnOOQFgMhB5wD6BTtGo6sMjJQv51kYk1VGFkfsTUprANQAxWt2hAqwqLA4ZsvrzkVPydc8-u9jS0MfJ05uCL_CMPG-4cPKc0etC50fY-hO7xZnS76lYfVEEw8dX40bmuvuFN5QaMfo37JXDbXJvzv0E_Z1cbE8v8puP19en5_dZk6WRmeETjkhHkVdoyybgkRTIxVaSwlifrIqlHQkJChyRhkDZUOEomn87HYOxQn7uM_dxv7n6NNgNyE537bU-X5MVqNGo1DNQrUXutinFH1jtzFsKE4Wwe5w2rU94LQ7nBa0nXHOvg-HBePjxtd_XQd-s-DTXvAUWj_9X6q9uLla_Lsl24eENPjff0Io_rClFlrZ-7tLK749PKD4cm8r8Qxf15ba</recordid><startdate>200401</startdate><enddate>200401</enddate><creator>Diedrichs, Holger</creator><creator>Chi, Mei</creator><creator>Boelck, Birgit</creator><creator>Mehlhorm, Uwe</creator><creator>Schwinger, Robert H.G.</creator><general>Blackwell Publishing Ltd</general><scope>BSCLL</scope><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>200401</creationdate><title>Increased regulatory activity of the calcineurin/NFAT pathway in human heart failure</title><author>Diedrichs, Holger ; Chi, Mei ; Boelck, Birgit ; Mehlhorm, Uwe ; Schwinger, Robert H.G.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4687-a1c5c33b3dd146f2a3fd1a27744031019254ca3405ac858806faa13ffe687cc13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Adult</topic><topic>Calcineurin</topic><topic>Calcineurin - genetics</topic><topic>Calcineurin - metabolism</topic><topic>Cardiomyopathy</topic><topic>Cardiomyopathy, Dilated - metabolism</topic><topic>Cell Nucleus - metabolism</topic><topic>DNA-Binding Proteins - genetics</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Female</topic><topic>GATA-4</topic><topic>GATA4 Transcription Factor</topic><topic>Heart failure</topic><topic>Humans</topic><topic>Hypertrophy</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Myocardium - metabolism</topic><topic>NFAT-3</topic><topic>NFATC Transcription Factors</topic><topic>Nuclear Proteins</topic><topic>RNA, Messenger - genetics</topic><topic>Signal Transduction - physiology</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Diedrichs, Holger</creatorcontrib><creatorcontrib>Chi, Mei</creatorcontrib><creatorcontrib>Boelck, Birgit</creatorcontrib><creatorcontrib>Mehlhorm, Uwe</creatorcontrib><creatorcontrib>Schwinger, Robert H.G.</creatorcontrib><collection>Istex</collection><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>European journal of heart failure</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Diedrichs, Holger</au><au>Chi, Mei</au><au>Boelck, Birgit</au><au>Mehlhorm, Uwe</au><au>Schwinger, Robert H.G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Increased regulatory activity of the calcineurin/NFAT pathway in human heart failure</atitle><jtitle>European journal of heart failure</jtitle><addtitle>European Journal of Heart Failure</addtitle><date>2004-01</date><risdate>2004</risdate><volume>6</volume><issue>1</issue><spage>3</spage><epage>9</epage><pages>3-9</pages><issn>1388-9842</issn><eissn>1879-0844</eissn><notes>ArticleID:EJHF2003-07-007</notes><notes>ark:/67375/WNG-3VXX13RW-9</notes><notes>istex:F8B228CB86883729B51CDB03413DBC54BA912B5F</notes><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>Background:
Cardiac hypertrophy may initiate progression to a compromised cardiac function. While the clinical consequences of hypertrophy are well understood, only little is known about the underlying molecular pathways. As reported from animal experiments, the Ca2+‐calmodulin activated phosphatase calcineurin and its downstream transcriptional effector NFAT have been implicated as transducers of the hypertrophic response.
Methods and results:
To study whether the calcineurin pathway is activated in human heart failure, we investigated samples of human left ventricular myocardium from patients with dilated (idiopathic) cardiomyopathy (DCM, NYHA IV, n=8) in comparison with non‐failing controls (NF, n=8). We not only analyzed the pathway by measuring the calcineurin activity, but also by determination of the protein expression of the calcineurin B subunit and additional key markers of the calcineurin signaling cascade (NFAT‐3, GATA‐4). Calcineurin enzymatic activity was increased by 80% in human dilated cardiomyopathy compared with non‐failing human hearts (135.424±11.69 and 83.484±1.81 nmol Pi/min per μl). This was in line with increased protein expression of calcineurin B in DCM (71.18+9.11 vs. 46.41±11.23 densitometric units (DU)/μg protein). In order to verify the activated calcineurin pathway as described in animal models, we compared the protein expression of NFAT‐3 in homogenates within nuclear extracts. In nuclear extracts the protein level of NFAT‐3 was increased in dilated cardiomyopathy compared with non‐failing myocardium (104.01±8.85 vs. 71.47±8.79 DU/μg protein). In contrast, in homogenates the expression of NFAT‐3 was higher in the non‐failing tissue indicating subcellular redistribution (19.56±3.36 vs. 25.84±3.16 DU/μg protein). The protein expression of GATA‐4 was increased in DCM (43.14±2.89 vs. 29.87±2.17 DU/μg protein).
Conclusions:
In human heart failure (DCM) the calcineurin signaling pathway is activated not only by an increased activity of calcineurin and expression of GATA‐4, but also by the shift from dephosphorylated NFAT‐3 to the nucleus indicating subcellular redistribution and regulatory activation.</abstract><cop>England</cop><pub>Blackwell Publishing Ltd</pub><pmid>15012912</pmid><doi>10.1016/j.ejheart.2003.07.007</doi><tpages>7</tpages></addata></record> |
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| ispartof | European journal of heart failure, 2004-01, Vol.6 (1), p.3-9 |
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| subjects | Adult Calcineurin Calcineurin - genetics Calcineurin - metabolism Cardiomyopathy Cardiomyopathy, Dilated - metabolism Cell Nucleus - metabolism DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Female GATA-4 GATA4 Transcription Factor Heart failure Humans Hypertrophy Male Middle Aged Myocardium - metabolism NFAT-3 NFATC Transcription Factors Nuclear Proteins RNA, Messenger - genetics Signal Transduction - physiology Transcription Factors - genetics Transcription Factors - metabolism |
| title | Increased regulatory activity of the calcineurin/NFAT pathway in human heart failure |
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