{"doi":"10.1371/journal.pone.0100179","title":"Cholinergic Signaling Exerts Protective Effects in Models of Sympathetic Hyperactivity-Induced Cardiac Dysfunction","abstract":null,"journal":"PLoS ONE","year":2014,"id":684355,"datarank":0.6846522287201755,"base_score":4.564348191467836,"endowment":4.564348191467836,"self_citation_contribution":0.6846522287201755,"citation_network_contribution":0.0,"self_endowment_contribution":0.6846522287201755,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":95,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":6,"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":1787858,"name":"Aline Lara","orcid":null,"position":1,"is_corresponding":false},{"id":1787860,"name":"Pedro W. M. Almeida","orcid":null,"position":2,"is_corresponding":false},{"id":1787863,"name":"Augusto Martins Lima","orcid":null,"position":3,"is_corresponding":false},{"id":1787865,"name":"Denis D. Damasceno","orcid":null,"position":4,"is_corresponding":false},{"id":1787867,"name":"Cibele Rocha-Resende","orcid":null,"position":5,"is_corresponding":false},{"id":1787868,"name":"Marina Ladeira","orcid":null,"position":6,"is_corresponding":false},{"id":293196,"name":"Rodrigo R. Resende","orcid":"0000-0002-2003-0739","position":7,"is_corresponding":false},{"id":1787870,"name":"Patricia M. Martinelli","orcid":null,"position":8,"is_corresponding":false},{"id":1787871,"name":"Marcos Barrouin Melo","orcid":null,"position":9,"is_corresponding":false},{"id":1787872,"name":"Patricia C. Brum","orcid":null,"position":10,"is_corresponding":false},{"id":1787873,"name":"Marco Antonio Peliky Fontes","orcid":null,"position":11,"is_corresponding":false},{"id":1787875,"name":"Robson A. Souza Santos","orcid":null,"position":12,"is_corresponding":false},{"id":247151,"name":"Marco A. M. Prado","orcid":"0000-0002-3028-5778","position":13,"is_corresponding":false},{"id":1787877,"name":"Silvia Guatimosim","orcid":null,"position":14,"is_corresponding":false},{"id":1787854,"name":"Mariana Gavioli","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Cholinergic Signaling Exerts Protective Effects in Models of Sympathetic Hyperactivity-Induced Cardiac Dysfunction","abstract":"Cholinergic control of the heart is exerted by two distinct branches; the autonomic component represented by the parasympathetic nervous system, and the recently described non-neuronal cardiomyocyte cholinergic machinery. Previous evidence has shown that reduced cholinergic function leads to deleterious effects on the myocardium. Yet, whether conditions of increased cholinergic signaling can offset the pathological remodeling induced by sympathetic hyperactivity, and its consequences for these two cholinergic axes are unknown. Here, we investigated two models of sympathetic hyperactivity: i) the chronic beta-adrenergic receptor stimulation evoked by isoproterenol (ISO), and ii) the α2A/α2C-adrenergic receptor knockout (KO) mice that lack pre-synaptic adrenergic receptors. In both models, cholinergic signaling was increased by administration of the cholinesterase inhibitor, pyridostigmine. First, we observed that isoproterenol produces an autonomic imbalance characterized by increased sympathetic and reduced parasympathetic tone. Under this condition transcripts for cholinergic proteins were upregulated in ventricular myocytes, indicating that non-neuronal cholinergic machinery is activated during adrenergic overdrive. Pyridostigmine treatment prevented the effects of ISO on autonomic function and on the ventricular cholinergic machinery, and inhibited cardiac remodeling. α2A/α2C-KO mice presented reduced ventricular contraction when compared to wild-type mice, and this dysfunction was also reversed by cholinesterase inhibition. Thus, the cardiac parasympathetic system and non-neuronal cardiomyocyte cholinergic machinery are modulated in opposite directions under conditions of increased sympathetic drive or ACh availability. Moreover, our data support the idea that pyridostigmine by restoring ACh availability is beneficial in heart disease.","is_dataset_classified":null,"base_score":4.564348191467836,"endowment":4.564348191467836,"datacite_reuse_total":6,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"24992197","pmcid":"PMC4081111","openalex_id":"https://openalex.org/W2019954233","authors":[],"funders":[{"funder_name":"FIC NIH HHS","grant_id":"R03 TW008425","title":null},{"funder_name":"National Institutes of Health","grant_id":"5R03TW008425-02","title":"Decreased Cholinergic Tone and Mitochondrial Dysfunction in Heart"}],"total_grants":2,"fwci":5.2492,"citation_percentile":0.96388899,"influential_citations":0,"citation_trend":[{"year":2014,"count":4},{"year":2015,"count":9},{"year":2016,"count":5},{"year":2017,"count":10},{"year":2018,"count":10},{"year":2019,"count":11},{"year":2020,"count":13},{"year":2021,"count":12},{"year":2022,"count":2},{"year":2023,"count":3},{"year":2024,"count":13},{"year":2025,"count":1},{"year":2026,"count":2}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0100179&type=printable","host_type":"journal"},{"url":"https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0100179&type=printable","host_type":"publisher"},{"url":"http://dx.plos.org/10.1371/journal.pone.0100179","host_type":"publisher"},{"url":"https://doi.org/10.1371/journal.pone.0100179","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/24992197","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/4081111","host_type":"repository"},{"url":"http://dx.doi.org/10.1371/journal.pone.0100179","host_type":"repository"},{"url":"https://doaj.org/article/c2ca11c35bd142bfba48e8d39b5bbbb8","host_type":"repository"},{"url":"https://ir.lib.uwo.ca/anatomypub/27","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC4081111","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC4081111?pdf=render","host_type":"Europe_PMC"},{"url":"https://dx.doi.org/10.1371/journal.pone.0100179","host_type":""},{"url":"https://ir.lib.uwo.ca/context/anatomypub/article/1028/viewcontent/PLOS_one.PDF","host_type":""},{"url":"https://doi.org/https://doi.org/10.1371/journal.pone.0100179","host_type":""}],"fields_of_study":["Cardiac electrophysiology and arrhythmias","Heart Rate Variability and Autonomic Control","Receptor Mechanisms and Signaling","0301 basic medicine","03 medical and health sciences","0303 health sciences"],"mesh_terms":["Animals","Autonomic Nervous System","Cardiotonic Agents","Cells, Cultured","Cholinesterase Inhibitors","Isoproterenol","Male","Mice, Inbred C57BL","Pyridostigmine Bromide","Signal Transduction","Rats, Wistar","Mice, Knockout","Cholinergic Agents","Myocytes, Cardiac","Mice","In Vitro Techniques"],"keywords":["Cholinergic","Pyridostigmine","Endocrinology","Internal medicine","Pyridostigmine Bromide","Adrenergic","Acetylcholine","Autonomic nervous system","Parasympathetic nervous system","Cholinergic neuron","Sympathetic nervous system","Stimulation","Medicine","Biology","Receptor","Heart rate","Blood pressure","Male","Cardiotonic Agents","PROTEIN EXPRESSION","Science","Cholinergic Agents","610","EXERCISE","In Vitro Techniques","RATS","Cell and Developmental Biology","Mice","DEFICITS","Animals","Myocytes, Cardiac","VESICULAR ACETYLCHOLINE TRANSPORTER","Rats, Wistar","Cells, Cultured","Mice, Knockout","CARVEDILOL","Q","R","Isoproterenol","CHRONIC HEART-FAILURE","HYPERTROPHY","RECEPTORS","Mice, Inbred C57BL","SURVIVAL","Cholinesterase Inhibitors","Anatomy","Research Article","Signal Transduction"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. 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