{"doi":"10.1073/pnas.97.3.1196","title":"Targeted inhibition of calcineurin prevents agonist-induced cardiomyocyte hypertrophy","abstract":"<jats:p>\n                    Cardiac hypertrophy is a major predictor of future morbidity and mortality. Recent investigation has centered around identifying the molecular signaling pathways that regulate cardiac myocyte reactivity with the goal of modulating pathologic hypertrophic programs. One potential regulator of cardiomyocyte hypertrophy is the calcium-sensitive phosphatase calcineurin. We show here that calcineurin enzymatic activity, mRNA, and protein levels are increased in cultured neonatal rat cardiomyocytes by hypertrophic agonists such as angiotensin II, phenylephrine, and 1% fetal bovine serum. This induction of calcineurin activity was associated with an increase in calcineurin Aβ (CnAβ) mRNA and protein, but not in CnAα or CnAγ. Agonist-dependent increases in calcineurin enzymatic activity were specifically inhibited with an adenovirus expressing a noncompetitive peptide inhibitor of calcineurin known as cain [Lai, M. M., Burnett, P. E., Wolosker, H., Blackshaw, S. &amp; Snyder, S. H. (1998)\n                    <jats:italic>J. Biol. Chem.</jats:italic>\n                    273, 18325–18331]. Targeted inhibition of calcineurin with cain or an adenovirus expressing only the calcineurin inhibitory domain of AKAP79 attenuated cardiomyocyte hypertrophy and atrial natriuretic factor expression in response to angiotensin II, phenylephrine, and 1% fetal bovine serum. These data demonstrate that calcineurin is an important regulator of cardiomyocyte hypertrophy in response to certain agonists and suggest that cyclosporin A and FK506 function to attenuate cardiac hypertrophy by specifically inhibiting calcineurin.\n                  </jats:p>","journal":"Proceedings of the National Academy of Sciences","year":2000,"id":615560,"datarank":0.8545640229758108,"base_score":5.697093486505405,"endowment":5.697093486505405,"self_citation_contribution":0.8545640229758108,"citation_network_contribution":0.0,"self_endowment_contribution":0.8545640229758108,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":297,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"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":1586710,"name":"Leon J. De Windt","orcid":null,"position":1,"is_corresponding":false},{"id":1586711,"name":"Hae W. Lim","orcid":null,"position":2,"is_corresponding":false},{"id":289834,"name":"Jeffery D. Molkentin","orcid":"0000-0002-3558-6529","position":3,"is_corresponding":false},{"id":1586709,"name":"Tyler Taigen","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Targeted inhibition of calcineurin prevents agonist-induced cardiomyocyte hypertrophy","abstract":"<jats:p>\n                    Cardiac hypertrophy is a major predictor of future morbidity and mortality. Recent investigation has centered around identifying the molecular signaling pathways that regulate cardiac myocyte reactivity with the goal of modulating pathologic hypertrophic programs. One potential regulator of cardiomyocyte hypertrophy is the calcium-sensitive phosphatase calcineurin. We show here that calcineurin enzymatic activity, mRNA, and protein levels are increased in cultured neonatal rat cardiomyocytes by hypertrophic agonists such as angiotensin II, phenylephrine, and 1% fetal bovine serum. This induction of calcineurin activity was associated with an increase in calcineurin Aβ (CnAβ) mRNA and protein, but not in CnAα or CnAγ. Agonist-dependent increases in calcineurin enzymatic activity were specifically inhibited with an adenovirus expressing a noncompetitive peptide inhibitor of calcineurin known as cain [Lai, M. M., Burnett, P. E., Wolosker, H., Blackshaw, S. &amp; Snyder, S. H. (1998)\n                    <jats:italic>J. Biol. Chem.</jats:italic>\n                    273, 18325–18331]. Targeted inhibition of calcineurin with cain or an adenovirus expressing only the calcineurin inhibitory domain of AKAP79 attenuated cardiomyocyte hypertrophy and atrial natriuretic factor expression in response to angiotensin II, phenylephrine, and 1% fetal bovine serum. These data demonstrate that calcineurin is an important regulator of cardiomyocyte hypertrophy in response to certain agonists and suggest that cyclosporin A and FK506 function to attenuate cardiac hypertrophy by specifically inhibiting calcineurin.\n                  </jats:p>","is_dataset_classified":null,"base_score":5.697093486505405,"endowment":5.697093486505405,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"10655507","pmcid":"PMC15566","openalex_id":"https://openalex.org/W2052863274","authors":[],"funders":[{"funder_name":"NHLBI NIH HHS","grant_id":"HL-69562","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"R01 HL062927","title":null},{"funder_name":"NIEHS NIH HHS","grant_id":"T32 ES007051","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"HL-62927","title":null},{"funder_name":"NIEHS NIH HHS","grant_id":"T32 ES07051","title":null}],"total_grants":5,"fwci":10.1911,"citation_percentile":0.98890047,"influential_citations":0,"citation_trend":[{"year":2012,"count":15},{"year":2013,"count":6},{"year":2014,"count":7},{"year":2015,"count":7},{"year":2016,"count":6},{"year":2017,"count":5},{"year":2018,"count":5},{"year":2019,"count":6},{"year":2020,"count":6},{"year":2021,"count":7},{"year":2022,"count":3},{"year":2023,"count":3},{"year":2024,"count":1},{"year":2025,"count":1}],"oa_status":"green","license":null,"oa_locations":[{"url":"https://pnas.org/doi/pdf/10.1073/pnas.97.3.1196","host_type":"publisher"},{"url":"https://doi.org/10.1073/pnas.97.3.1196","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/10655507","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/15566","host_type":"repository"}],"fields_of_study":["Signaling Pathways in Disease","Cardiac Fibrosis and Remodeling","Cardiomyopathy and Myosin Studies"],"mesh_terms":["Adenoviridae","Angiotensin II","Animals","Carrier Proteins","Cattle","Cells, Cultured","DNA-Binding Proteins","Fetal Blood","Gene Expression Regulation","Genes","Genetic Vectors","Cardiomegaly","Hypertrophy","Myocardium","Atrial Natriuretic Factor","Nuclear Proteins","Phenylephrine","Transcription Factors","Transfection","Genetic Therapy","Calcineurin","Reverse Transcriptase Polymerase Chain Reaction","NFATC Transcription Factors","Apoptosis Regulatory Proteins","Rats","Calcineurin Inhibitors"],"keywords":["Calcineurin","Endocrinology","Internal medicine","Phenylephrine","Muscle hypertrophy","Phosphatase","Angiotensin II","Biology","NFAT","Agonist","Chemistry","Pharmacology","Receptor","Medicine","Enzyme","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":"2026-08-02T20:21:42.039113Z","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":[]}