{"doi":"10.1016/j.ejheart.2003.07.007","title":"Increased Regulatory Activity of the Calcineurin/NFAT Pathway in Human Heart Failure","abstract":"<jats:title>Abstract</jats:title>\n                  <jats:sec>\n                    <jats:title>Background</jats:title>\n                    <jats:p>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.</jats:p>\n                  </jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results</jats:title>\n                    <jats:p>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).</jats:p>\n                  </jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions</jats:title>\n                    <jats:p>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.</jats:p>\n                  </jats:sec>","journal":"European Journal of Heart Failure","year":2004,"id":591989,"datarank":3.7901721395607213,"base_score":4.304065093204169,"endowment":4.304065093204169,"self_citation_contribution":0.6456097639806255,"citation_network_contribution":3.1445623755800955,"self_endowment_contribution":0.6456097639806255,"citer_contribution":3.1445623755800955,"corpus_percentile":null,"corpus_rank":null,"citation_count":73,"citer_count":69,"citers_with_citation_signal":63,"citers_with_endowment":63,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1514738,"name":"Mei Chi","orcid":null,"position":1,"is_corresponding":false},{"id":1514739,"name":"Birgit Boelck","orcid":null,"position":2,"is_corresponding":false},{"id":1514740,"name":"Uwe Mehlhorm","orcid":null,"position":3,"is_corresponding":false},{"id":1514741,"name":"Robert H.G. Schwinger","orcid":null,"position":4,"is_corresponding":false},{"id":1514737,"name":"Holger Diedrichs","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Increased Regulatory Activity of the Calcineurin/NFAT Pathway in Human Heart Failure","abstract":"<jats:title>Abstract</jats:title>\n                  <jats:sec>\n                    <jats:title>Background</jats:title>\n                    <jats:p>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.</jats:p>\n                  </jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results</jats:title>\n                    <jats:p>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).</jats:p>\n                  </jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions</jats:title>\n                    <jats:p>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.</jats:p>\n                  </jats:sec>","is_dataset_classified":null,"base_score":4.304065093204169,"endowment":4.304065093204169,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"15012912","pmcid":null,"openalex_id":"https://openalex.org/W2035055285","authors":[],"funders":[],"total_grants":0,"fwci":1.3006,"citation_percentile":0.78224386,"influential_citations":0,"citation_trend":[{"year":2012,"count":8},{"year":2013,"count":1},{"year":2014,"count":4},{"year":2015,"count":4},{"year":2016,"count":6},{"year":2017,"count":4},{"year":2018,"count":3},{"year":2019,"count":1},{"year":2020,"count":4},{"year":2021,"count":1},{"year":2022,"count":2},{"year":2023,"count":1},{"year":2024,"count":2},{"year":2025,"count":1},{"year":2026,"count":1}],"oa_status":"closed","license":"https://academic.oup.com/pages/standard-publication-reuse-rights","oa_locations":[{"url":"https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1016%2Fj.ejheart.2003.07.007","host_type":"publisher"},{"url":"https://academic.oup.com/eurjhf/article-pdf/6/1/3/66648817/eurjhf_6_1_3.pdf","host_type":"publisher"},{"url":"https://doi.org/10.1016/j.ejheart.2003.07.007","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/15012912","host_type":"repository"}],"fields_of_study":["Signaling Pathways in Disease","Cardiac Fibrosis and Remodeling","Cardiovascular Function and Risk Factors","Adult","Calcineurin","Cardiomyopathy, Dilated","Cell Nucleus","DNA-Binding Proteins","Female","GATA4 Transcription Factor","Humans","Male","Middle Aged","Myocardium","NFATC Transcription Factors","Nuclear Proteins","RNA, Messenger","Signal Transduction","Transcription Factors"],"mesh_terms":["Adult","Cardiomyopathy, Dilated","Cell Nucleus","DNA-Binding Proteins","Female","Humans","Male","Middle Aged","Myocardium","Nuclear Proteins","RNA, Messenger","Transcription Factors","Signal Transduction","Calcineurin","NFATC Transcription Factors","GATA4 Transcription Factor"],"keywords":["Calcineurin","NFAT","Dilated cardiomyopathy","Medicine","Heart failure","Muscle hypertrophy","Internal medicine","Cardiomyopathy","Endocrinology","Phosphatase","Myocyte","Enzyme","Biology","Biochemistry","Transplantation"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-26T11:42:07.031792Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}