Cholinergic signaling exerts protective effects in models of sympathetic hyperactivity-induced cardiac dysfunction.
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 deleter...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4081111?pdf=render |
| _version_ | 1811290856894758912 |
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| author | Mariana Gavioli Aline Lara Pedro W M Almeida Augusto Martins Lima Denis D Damasceno Cibele Rocha-Resende Marina Ladeira Rodrigo R Resende Patricia M Martinelli Marcos Barrouin Melo Patricia C Brum Marco Antonio Peliky Fontes Robson A Souza Santos Marco A M Prado Silvia Guatimosim |
| author_facet | Mariana Gavioli Aline Lara Pedro W M Almeida Augusto Martins Lima Denis D Damasceno Cibele Rocha-Resende Marina Ladeira Rodrigo R Resende Patricia M Martinelli Marcos Barrouin Melo Patricia C Brum Marco Antonio Peliky Fontes Robson A Souza Santos Marco A M Prado Silvia Guatimosim |
| author_sort | Mariana Gavioli |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T04:19:47Z |
| format | Article |
| id | doaj.art-c2ca11c35bd142bfba48e8d39b5bbbb8 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-13T04:19:47Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-c2ca11c35bd142bfba48e8d39b5bbbb82022-12-22T03:02:49ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0197e10017910.1371/journal.pone.0100179Cholinergic signaling exerts protective effects in models of sympathetic hyperactivity-induced cardiac dysfunction.Mariana GavioliAline LaraPedro W M AlmeidaAugusto Martins LimaDenis D DamascenoCibele Rocha-ResendeMarina LadeiraRodrigo R ResendePatricia M MartinelliMarcos Barrouin MeloPatricia C BrumMarco Antonio Peliky FontesRobson A Souza SantosMarco A M PradoSilvia GuatimosimCholinergic 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.http://europepmc.org/articles/PMC4081111?pdf=render |
| spellingShingle | Mariana Gavioli Aline Lara Pedro W M Almeida Augusto Martins Lima Denis D Damasceno Cibele Rocha-Resende Marina Ladeira Rodrigo R Resende Patricia M Martinelli Marcos Barrouin Melo Patricia C Brum Marco Antonio Peliky Fontes Robson A Souza Santos Marco A M Prado Silvia Guatimosim Cholinergic signaling exerts protective effects in models of sympathetic hyperactivity-induced cardiac dysfunction. PLoS ONE |
| title | Cholinergic signaling exerts protective effects in models of sympathetic hyperactivity-induced cardiac dysfunction. |
| title_full | Cholinergic signaling exerts protective effects in models of sympathetic hyperactivity-induced cardiac dysfunction. |
| title_fullStr | Cholinergic signaling exerts protective effects in models of sympathetic hyperactivity-induced cardiac dysfunction. |
| title_full_unstemmed | Cholinergic signaling exerts protective effects in models of sympathetic hyperactivity-induced cardiac dysfunction. |
| title_short | Cholinergic signaling exerts protective effects in models of sympathetic hyperactivity-induced cardiac dysfunction. |
| title_sort | cholinergic signaling exerts protective effects in models of sympathetic hyperactivity induced cardiac dysfunction |
| url | http://europepmc.org/articles/PMC4081111?pdf=render |
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