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.
authors.affiliation: Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Mariana
authors.initials: M
authors.lastname: Gavioli
authors.affiliation: Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Aline
authors.initials: A
authors.lastname: Lara
authors.affiliation: Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Pedro W M
authors.initials: PW
authors.lastname: Almeida
authors.affiliation: Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; National Institute of Science and Technology in Nanobiopharmaceutics, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Augusto Martins
authors.initials: AM
authors.lastname: Lima
authors.affiliation: Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Denis D
authors.initials: DD
authors.lastname: Damasceno
authors.affiliation: Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Cibele
authors.initials: C
authors.lastname: Rocha-Resende
authors.affiliation: Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Marina
authors.initials: M
authors.lastname: Ladeira
authors.affiliation: Department of Biochemistry, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Rodrigo R
authors.initials: RR
authors.lastname: Resende
authors.affiliation: Department of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Martinelli
authors.affiliation: Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; National Institute of Science and Technology in Nanobiopharmaceutics, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Marcos Barrouin
authors.initials: MB
authors.lastname: Melo
authors.affiliation: School of Physical Education and Sport, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Brum
authors.affiliation: Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; National Institute of Science and Technology in Nanobiopharmaceutics, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Marco Antonio Peliky
authors.initials: MA
authors.lastname: Fontes
authors.affiliation: Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; National Institute of Science and Technology in Nanobiopharmaceutics, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Robson A
authors.initials: RA
authors.lastname: Souza Santos
authors.affiliation: Robarts Research Institute, University of Western Ontario, Department of Physiology and Pharmacology, Department of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Canada.
authors.forename: Marco A M
authors.initials: MA
authors.lastname: Prado
authors.affiliation: Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; National Institute of Science and Technology in Nanobiopharmaceutics, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Silvia
authors.initials: S
authors.lastname: Guatimosim
mesh_terms: D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D018678:Cholinergic Agents / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000187:drug effects; D011729:Pyridostigmine Bromide / Q000494:pharmacology*; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; D018678:Cholinergic Agents; D002800:Cholinesterase Inhibitors; D011729:Pyridostigmine Bromide; D007545:Isoproterenol